Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2
Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. I...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Ma, Rui [verfasserIn] |
|---|
| Format: |
E-Artikel |
|---|---|
| Sprache: |
Englisch |
| Erschienen: |
2018transfer abstract |
|---|
| Schlagwörter: |
|---|
| Umfang: |
6 |
|---|
| Übergeordnetes Werk: |
Enthalten in: Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag - Zhang, Zhikun ELSEVIER, 2019, BBRC, Orlando, Fla |
|---|---|
| Übergeordnetes Werk: |
volume:503 ; year:2018 ; number:4 ; day:18 ; month:09 ; pages:2912-2917 ; extent:6 |
| Links: |
|---|
| DOI / URN: |
10.1016/j.bbrc.2018.08.068 |
|---|
| Katalog-ID: |
ELV043960758 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | ELV043960758 | ||
| 003 | DE-627 | ||
| 005 | 20230626004427.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 181113s2018 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1016/j.bbrc.2018.08.068 |2 doi | |
| 028 | 5 | 2 | |a GBV00000000000374.pica |
| 035 | |a (DE-627)ELV043960758 | ||
| 035 | |a (ELSEVIER)S0006-291X(18)31750-9 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 082 | 0 | 4 | |a 670 |q VZ |
| 084 | |a 51.60 |2 bkl | ||
| 084 | |a 58.45 |2 bkl | ||
| 100 | 1 | |a Ma, Rui |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 |
| 264 | 1 | |c 2018transfer abstract | |
| 300 | |a 6 | ||
| 336 | |a nicht spezifiziert |b zzz |2 rdacontent | ||
| 337 | |a nicht spezifiziert |b z |2 rdamedia | ||
| 338 | |a nicht spezifiziert |b zu |2 rdacarrier | ||
| 520 | |a Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. | ||
| 520 | |a Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. | ||
| 650 | 7 | |a R132H |2 Elsevier | |
| 650 | 7 | |a AG-881 |2 Elsevier | |
| 650 | 7 | |a IDH1 |2 Elsevier | |
| 650 | 7 | |a IDH2 |2 Elsevier | |
| 650 | 7 | |a R140Q |2 Elsevier | |
| 700 | 1 | |a Yun, Cai-Hong |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Academic Press |a Zhang, Zhikun ELSEVIER |t Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag |d 2019 |d BBRC |g Orlando, Fla |w (DE-627)ELV002811154 |
| 773 | 1 | 8 | |g volume:503 |g year:2018 |g number:4 |g day:18 |g month:09 |g pages:2912-2917 |g extent:6 |
| 856 | 4 | 0 | |u https://doi.org/10.1016/j.bbrc.2018.08.068 |3 Volltext |
| 912 | |a GBV_USEFLAG_U | ||
| 912 | |a GBV_ELV | ||
| 912 | |a SYSFLAG_U | ||
| 936 | b | k | |a 51.60 |j Keramische Werkstoffe |j Hartstoffe |x Werkstoffkunde |q VZ |
| 936 | b | k | |a 58.45 |j Gesteinshüttenkunde |q VZ |
| 951 | |a AR | ||
| 952 | |d 503 |j 2018 |e 4 |b 18 |c 0918 |h 2912-2917 |g 6 | ||
| author_variant |
r m rm |
|---|---|
| matchkey_str |
maruiyuncaihong:2018----:rsasrcueopndihbtrg8icmlxihu |
| hierarchy_sort_str |
2018transfer abstract |
| bklnumber |
51.60 58.45 |
| publishDate |
2018 |
| allfields |
10.1016/j.bbrc.2018.08.068 doi GBV00000000000374.pica (DE-627)ELV043960758 (ELSEVIER)S0006-291X(18)31750-9 DE-627 ger DE-627 rakwb eng 670 VZ 51.60 bkl 58.45 bkl Ma, Rui verfasserin aut Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 2018transfer abstract 6 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Elsevier Yun, Cai-Hong oth Enthalten in Academic Press Zhang, Zhikun ELSEVIER Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag 2019 BBRC Orlando, Fla (DE-627)ELV002811154 volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 https://doi.org/10.1016/j.bbrc.2018.08.068 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 51.60 Keramische Werkstoffe Hartstoffe Werkstoffkunde VZ 58.45 Gesteinshüttenkunde VZ AR 503 2018 4 18 0918 2912-2917 6 |
| spelling |
10.1016/j.bbrc.2018.08.068 doi GBV00000000000374.pica (DE-627)ELV043960758 (ELSEVIER)S0006-291X(18)31750-9 DE-627 ger DE-627 rakwb eng 670 VZ 51.60 bkl 58.45 bkl Ma, Rui verfasserin aut Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 2018transfer abstract 6 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Elsevier Yun, Cai-Hong oth Enthalten in Academic Press Zhang, Zhikun ELSEVIER Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag 2019 BBRC Orlando, Fla (DE-627)ELV002811154 volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 https://doi.org/10.1016/j.bbrc.2018.08.068 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 51.60 Keramische Werkstoffe Hartstoffe Werkstoffkunde VZ 58.45 Gesteinshüttenkunde VZ AR 503 2018 4 18 0918 2912-2917 6 |
| allfields_unstemmed |
10.1016/j.bbrc.2018.08.068 doi GBV00000000000374.pica (DE-627)ELV043960758 (ELSEVIER)S0006-291X(18)31750-9 DE-627 ger DE-627 rakwb eng 670 VZ 51.60 bkl 58.45 bkl Ma, Rui verfasserin aut Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 2018transfer abstract 6 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Elsevier Yun, Cai-Hong oth Enthalten in Academic Press Zhang, Zhikun ELSEVIER Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag 2019 BBRC Orlando, Fla (DE-627)ELV002811154 volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 https://doi.org/10.1016/j.bbrc.2018.08.068 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 51.60 Keramische Werkstoffe Hartstoffe Werkstoffkunde VZ 58.45 Gesteinshüttenkunde VZ AR 503 2018 4 18 0918 2912-2917 6 |
| allfieldsGer |
10.1016/j.bbrc.2018.08.068 doi GBV00000000000374.pica (DE-627)ELV043960758 (ELSEVIER)S0006-291X(18)31750-9 DE-627 ger DE-627 rakwb eng 670 VZ 51.60 bkl 58.45 bkl Ma, Rui verfasserin aut Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 2018transfer abstract 6 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Elsevier Yun, Cai-Hong oth Enthalten in Academic Press Zhang, Zhikun ELSEVIER Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag 2019 BBRC Orlando, Fla (DE-627)ELV002811154 volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 https://doi.org/10.1016/j.bbrc.2018.08.068 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 51.60 Keramische Werkstoffe Hartstoffe Werkstoffkunde VZ 58.45 Gesteinshüttenkunde VZ AR 503 2018 4 18 0918 2912-2917 6 |
| allfieldsSound |
10.1016/j.bbrc.2018.08.068 doi GBV00000000000374.pica (DE-627)ELV043960758 (ELSEVIER)S0006-291X(18)31750-9 DE-627 ger DE-627 rakwb eng 670 VZ 51.60 bkl 58.45 bkl Ma, Rui verfasserin aut Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 2018transfer abstract 6 nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Elsevier Yun, Cai-Hong oth Enthalten in Academic Press Zhang, Zhikun ELSEVIER Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag 2019 BBRC Orlando, Fla (DE-627)ELV002811154 volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 https://doi.org/10.1016/j.bbrc.2018.08.068 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U 51.60 Keramische Werkstoffe Hartstoffe Werkstoffkunde VZ 58.45 Gesteinshüttenkunde VZ AR 503 2018 4 18 0918 2912-2917 6 |
| language |
English |
| source |
Enthalten in Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag Orlando, Fla volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 |
| sourceStr |
Enthalten in Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag Orlando, Fla volume:503 year:2018 number:4 day:18 month:09 pages:2912-2917 extent:6 |
| format_phy_str_mv |
Article |
| bklname |
Keramische Werkstoffe Hartstoffe Gesteinshüttenkunde |
| institution |
findex.gbv.de |
| topic_facet |
R132H AG-881 IDH1 IDH2 R140Q |
| dewey-raw |
670 |
| isfreeaccess_bool |
false |
| container_title |
Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag |
| authorswithroles_txt_mv |
Ma, Rui @@aut@@ Yun, Cai-Hong @@oth@@ |
| publishDateDaySort_date |
2018-01-18T00:00:00Z |
| hierarchy_top_id |
ELV002811154 |
| dewey-sort |
3670 |
| id |
ELV043960758 |
| language_de |
englisch |
| fullrecord |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">ELV043960758</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230626004427.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">181113s2018 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.bbrc.2018.08.068</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">GBV00000000000374.pica</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV043960758</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S0006-291X(18)31750-9</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">670</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">51.60</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">58.45</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Ma, Rui</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018transfer abstract</subfield></datafield><datafield tag="300" ind1=" " ind2=" "><subfield code="a">6</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">z</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zu</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2.</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">R132H</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">AG-881</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">IDH1</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">IDH2</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">R140Q</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yun, Cai-Hong</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Academic Press</subfield><subfield code="a">Zhang, Zhikun ELSEVIER</subfield><subfield code="t">Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag</subfield><subfield code="d">2019</subfield><subfield code="d">BBRC</subfield><subfield code="g">Orlando, Fla</subfield><subfield code="w">(DE-627)ELV002811154</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:503</subfield><subfield code="g">year:2018</subfield><subfield code="g">number:4</subfield><subfield code="g">day:18</subfield><subfield code="g">month:09</subfield><subfield code="g">pages:2912-2917</subfield><subfield code="g">extent:6</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.bbrc.2018.08.068</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">51.60</subfield><subfield code="j">Keramische Werkstoffe</subfield><subfield code="j">Hartstoffe</subfield><subfield code="x">Werkstoffkunde</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">58.45</subfield><subfield code="j">Gesteinshüttenkunde</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">503</subfield><subfield code="j">2018</subfield><subfield code="e">4</subfield><subfield code="b">18</subfield><subfield code="c">0918</subfield><subfield code="h">2912-2917</subfield><subfield code="g">6</subfield></datafield></record></collection>
|
| author |
Ma, Rui |
| spellingShingle |
Ma, Rui ddc 670 bkl 51.60 bkl 58.45 Elsevier R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 |
| authorStr |
Ma, Rui |
| ppnlink_with_tag_str_mv |
@@773@@(DE-627)ELV002811154 |
| format |
electronic Article |
| dewey-ones |
670 - Manufacturing |
| delete_txt_mv |
keep |
| author_role |
aut |
| collection |
elsevier |
| remote_str |
true |
| illustrated |
Not Illustrated |
| topic_title |
670 VZ 51.60 bkl 58.45 bkl Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q Elsevier |
| topic |
ddc 670 bkl 51.60 bkl 58.45 Elsevier R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q |
| topic_unstemmed |
ddc 670 bkl 51.60 bkl 58.45 Elsevier R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q |
| topic_browse |
ddc 670 bkl 51.60 bkl 58.45 Elsevier R132H Elsevier AG-881 Elsevier IDH1 Elsevier IDH2 Elsevier R140Q |
| format_facet |
Elektronische Aufsätze Aufsätze Elektronische Ressource |
| format_main_str_mv |
Text Zeitschrift/Artikel |
| carriertype_str_mv |
zu |
| author2_variant |
c h y chy |
| hierarchy_parent_title |
Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag |
| hierarchy_parent_id |
ELV002811154 |
| dewey-tens |
670 - Manufacturing |
| hierarchy_top_title |
Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag |
| isfreeaccess_txt |
false |
| familylinks_str_mv |
(DE-627)ELV002811154 |
| title |
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 |
| ctrlnum |
(DE-627)ELV043960758 (ELSEVIER)S0006-291X(18)31750-9 |
| title_full |
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 |
| author_sort |
Ma, Rui |
| journal |
Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag |
| journalStr |
Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag |
| lang_code |
eng |
| isOA_bool |
false |
| dewey-hundreds |
600 - Technology |
| recordtype |
marc |
| publishDateSort |
2018 |
| contenttype_str_mv |
zzz |
| container_start_page |
2912 |
| author_browse |
Ma, Rui |
| container_volume |
503 |
| physical |
6 |
| class |
670 VZ 51.60 bkl 58.45 bkl |
| format_se |
Elektronische Aufsätze |
| author-letter |
Ma, Rui |
| doi_str_mv |
10.1016/j.bbrc.2018.08.068 |
| dewey-full |
670 |
| title_sort |
crystal structures of pan-idh inhibitor ag-881 in complex with mutant human idh1 and idh2 |
| title_auth |
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 |
| abstract |
Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. |
| abstractGer |
Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. |
| abstract_unstemmed |
Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2. |
| collection_details |
GBV_USEFLAG_U GBV_ELV SYSFLAG_U |
| container_issue |
4 |
| title_short |
Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2 |
| url |
https://doi.org/10.1016/j.bbrc.2018.08.068 |
| remote_bool |
true |
| author2 |
Yun, Cai-Hong |
| author2Str |
Yun, Cai-Hong |
| ppnlink |
ELV002811154 |
| mediatype_str_mv |
z |
| isOA_txt |
false |
| hochschulschrift_bool |
false |
| author2_role |
oth |
| doi_str |
10.1016/j.bbrc.2018.08.068 |
| up_date |
2024-07-06T20:13:02.227Z |
| _version_ |
1803861918721507328 |
| fullrecord_marcxml |
<?xml version="1.0" encoding="UTF-8"?><collection xmlns="http://www.loc.gov/MARC21/slim"><record><leader>01000caa a22002652 4500</leader><controlfield tag="001">ELV043960758</controlfield><controlfield tag="003">DE-627</controlfield><controlfield tag="005">20230626004427.0</controlfield><controlfield tag="007">cr uuu---uuuuu</controlfield><controlfield tag="008">181113s2018 xx |||||o 00| ||eng c</controlfield><datafield tag="024" ind1="7" ind2=" "><subfield code="a">10.1016/j.bbrc.2018.08.068</subfield><subfield code="2">doi</subfield></datafield><datafield tag="028" ind1="5" ind2="2"><subfield code="a">GBV00000000000374.pica</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(DE-627)ELV043960758</subfield></datafield><datafield tag="035" ind1=" " ind2=" "><subfield code="a">(ELSEVIER)S0006-291X(18)31750-9</subfield></datafield><datafield tag="040" ind1=" " ind2=" "><subfield code="a">DE-627</subfield><subfield code="b">ger</subfield><subfield code="c">DE-627</subfield><subfield code="e">rakwb</subfield></datafield><datafield tag="041" ind1=" " ind2=" "><subfield code="a">eng</subfield></datafield><datafield tag="082" ind1="0" ind2="4"><subfield code="a">670</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">51.60</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="084" ind1=" " ind2=" "><subfield code="a">58.45</subfield><subfield code="2">bkl</subfield></datafield><datafield tag="100" ind1="1" ind2=" "><subfield code="a">Ma, Rui</subfield><subfield code="e">verfasserin</subfield><subfield code="4">aut</subfield></datafield><datafield tag="245" ind1="1" ind2="0"><subfield code="a">Crystal structures of pan-IDH inhibitor AG-881 in complex with mutant human IDH1 and IDH2</subfield></datafield><datafield tag="264" ind1=" " ind2="1"><subfield code="c">2018transfer abstract</subfield></datafield><datafield tag="300" ind1=" " ind2=" "><subfield code="a">6</subfield></datafield><datafield tag="336" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zzz</subfield><subfield code="2">rdacontent</subfield></datafield><datafield tag="337" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">z</subfield><subfield code="2">rdamedia</subfield></datafield><datafield tag="338" ind1=" " ind2=" "><subfield code="a">nicht spezifiziert</subfield><subfield code="b">zu</subfield><subfield code="2">rdacarrier</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">Some mutations of isocitrate dehydrogenase 1 and 2 observed in multiple kinds of malignant tumors can lead to a neomorphic enzyme activity that converts alpha-ketoglutarate (α-KG) to 2-hydroxyglutarate (2-HG). As an oncometabolite, 2-HG can cause epigenetic changes and impair cell differentiation. Inhibiting the activity of isocitrate dehydrogenase mutants (mIDH) is considered to be an effective therapy for the treatment of mIDH positive cancers, including glioma and acute myeloid leukemia (AML). The presently disclosed allosteric inhibitors work only on one of the mIDH1 and mIDH2, and it is shown that mIDH1 and mIDH2 have different allosteric inhibition pockets. However, AG-881 from Agios Pharmaceuticals was found to be a pan-IDH inhibitor against both mIDH1 and mIDH2, and is undergoing Phase I clinical trials for tumors with an IDH1 and/or IDH2 mutation. To understand the binding mode of AG-881 to mIDHs, we solved the crystal structures of IDH1-R132H/NADPH/AG-881 and IDH2-R140Q/NADPH/AG-881 complexes, and acquired the IC50 values of AG-881 for IDH1-R132H and IDH2-R140Q homodimers after different pre-incubation times. Our data show that AG-881 binds IDH1-R132H and IDH2-R140Q in the same allosteric pockets and that the subtle difference in the pockets of these two proteins may contribute to their remarkably different inhibitory kinetics by AG-881. The structural pharmacological data provided in this report may benefit the future development of pan-IDH inhibitors targeting mIDH1 and mIDH2.</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">R132H</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">AG-881</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">IDH1</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">IDH2</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">R140Q</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Yun, Cai-Hong</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Academic Press</subfield><subfield code="a">Zhang, Zhikun ELSEVIER</subfield><subfield code="t">Preparation and characterization of glass-ceramics via co-sintering of coal fly ash and oil shale ash-derived amorphous slag</subfield><subfield code="d">2019</subfield><subfield code="d">BBRC</subfield><subfield code="g">Orlando, Fla</subfield><subfield code="w">(DE-627)ELV002811154</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:503</subfield><subfield code="g">year:2018</subfield><subfield code="g">number:4</subfield><subfield code="g">day:18</subfield><subfield code="g">month:09</subfield><subfield code="g">pages:2912-2917</subfield><subfield code="g">extent:6</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.bbrc.2018.08.068</subfield><subfield code="3">Volltext</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_USEFLAG_U</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">GBV_ELV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SYSFLAG_U</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">51.60</subfield><subfield code="j">Keramische Werkstoffe</subfield><subfield code="j">Hartstoffe</subfield><subfield code="x">Werkstoffkunde</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">58.45</subfield><subfield code="j">Gesteinshüttenkunde</subfield><subfield code="q">VZ</subfield></datafield><datafield tag="951" ind1=" " ind2=" "><subfield code="a">AR</subfield></datafield><datafield tag="952" ind1=" " ind2=" "><subfield code="d">503</subfield><subfield code="j">2018</subfield><subfield code="e">4</subfield><subfield code="b">18</subfield><subfield code="c">0918</subfield><subfield code="h">2912-2917</subfield><subfield code="g">6</subfield></datafield></record></collection>
|
| score |
7.4010878 |