Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile
We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Sestito, Simona [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2021transfer abstract |
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| Übergeordnetes Werk: |
Enthalten in: Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles - Jose, Ajay ELSEVIER, 2018, Amsterdam [u.a.] |
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| Übergeordnetes Werk: |
volume:226 ; year:2021 ; day:15 ; month:12 ; pages:0 |
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| DOI / URN: |
10.1016/j.ejmech.2021.113895 |
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| 245 | 1 | 0 | |a Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile |
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| 520 | |a We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. | ||
| 520 | |a We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. | ||
| 650 | 7 | |a Ewing sarcoma |2 Elsevier | |
| 650 | 7 | |a Dual inhibitors |2 Elsevier | |
| 650 | 7 | |a Kinases |2 Elsevier | |
| 650 | 7 | |a Multitarget compounds |2 Elsevier | |
| 650 | 7 | |a Aurora A |2 Elsevier | |
| 650 | 7 | |a PDK1 |2 Elsevier | |
| 700 | 1 | |a Bacci, Andrea |4 oth | |
| 700 | 1 | |a Chiarugi, Sara |4 oth | |
| 700 | 1 | |a Runfola, Massimiliano |4 oth | |
| 700 | 1 | |a Gado, Francesca |4 oth | |
| 700 | 1 | |a Margheritis, Eleonora |4 oth | |
| 700 | 1 | |a Gul, Sheraz |4 oth | |
| 700 | 1 | |a Riveiro, Maria E. |4 oth | |
| 700 | 1 | |a Vazquez, Ramiro |4 oth | |
| 700 | 1 | |a Huguet, Samuel |4 oth | |
| 700 | 1 | |a Manera, Clementina |4 oth | |
| 700 | 1 | |a Rezai, Keyvan |4 oth | |
| 700 | 1 | |a Garau, Gianpiero |4 oth | |
| 700 | 1 | |a Rapposelli, Simona |4 oth | |
| 773 | 0 | 8 | |i Enthalten in |n Elsevier Science |a Jose, Ajay ELSEVIER |t Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles |d 2018 |g Amsterdam [u.a.] |w (DE-627)ELV000457477 |
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10.1016/j.ejmech.2021.113895 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001663.pica (DE-627)ELV055889166 (ELSEVIER)S0223-5234(21)00744-3 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Sestito, Simona verfasserin aut Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. Ewing sarcoma Elsevier Dual inhibitors Elsevier Kinases Elsevier Multitarget compounds Elsevier Aurora A Elsevier PDK1 Elsevier Bacci, Andrea oth Chiarugi, Sara oth Runfola, Massimiliano oth Gado, Francesca oth Margheritis, Eleonora oth Gul, Sheraz oth Riveiro, Maria E. oth Vazquez, Ramiro oth Huguet, Samuel oth Manera, Clementina oth Rezai, Keyvan oth Garau, Gianpiero oth Rapposelli, Simona oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:226 year:2021 day:15 month:12 pages:0 https://doi.org/10.1016/j.ejmech.2021.113895 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 226 2021 15 1215 0 |
| spelling |
10.1016/j.ejmech.2021.113895 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001663.pica (DE-627)ELV055889166 (ELSEVIER)S0223-5234(21)00744-3 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Sestito, Simona verfasserin aut Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. Ewing sarcoma Elsevier Dual inhibitors Elsevier Kinases Elsevier Multitarget compounds Elsevier Aurora A Elsevier PDK1 Elsevier Bacci, Andrea oth Chiarugi, Sara oth Runfola, Massimiliano oth Gado, Francesca oth Margheritis, Eleonora oth Gul, Sheraz oth Riveiro, Maria E. oth Vazquez, Ramiro oth Huguet, Samuel oth Manera, Clementina oth Rezai, Keyvan oth Garau, Gianpiero oth Rapposelli, Simona oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:226 year:2021 day:15 month:12 pages:0 https://doi.org/10.1016/j.ejmech.2021.113895 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 226 2021 15 1215 0 |
| allfields_unstemmed |
10.1016/j.ejmech.2021.113895 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001663.pica (DE-627)ELV055889166 (ELSEVIER)S0223-5234(21)00744-3 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Sestito, Simona verfasserin aut Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. Ewing sarcoma Elsevier Dual inhibitors Elsevier Kinases Elsevier Multitarget compounds Elsevier Aurora A Elsevier PDK1 Elsevier Bacci, Andrea oth Chiarugi, Sara oth Runfola, Massimiliano oth Gado, Francesca oth Margheritis, Eleonora oth Gul, Sheraz oth Riveiro, Maria E. oth Vazquez, Ramiro oth Huguet, Samuel oth Manera, Clementina oth Rezai, Keyvan oth Garau, Gianpiero oth Rapposelli, Simona oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:226 year:2021 day:15 month:12 pages:0 https://doi.org/10.1016/j.ejmech.2021.113895 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 226 2021 15 1215 0 |
| allfieldsGer |
10.1016/j.ejmech.2021.113895 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001663.pica (DE-627)ELV055889166 (ELSEVIER)S0223-5234(21)00744-3 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Sestito, Simona verfasserin aut Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. Ewing sarcoma Elsevier Dual inhibitors Elsevier Kinases Elsevier Multitarget compounds Elsevier Aurora A Elsevier PDK1 Elsevier Bacci, Andrea oth Chiarugi, Sara oth Runfola, Massimiliano oth Gado, Francesca oth Margheritis, Eleonora oth Gul, Sheraz oth Riveiro, Maria E. oth Vazquez, Ramiro oth Huguet, Samuel oth Manera, Clementina oth Rezai, Keyvan oth Garau, Gianpiero oth Rapposelli, Simona oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:226 year:2021 day:15 month:12 pages:0 https://doi.org/10.1016/j.ejmech.2021.113895 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 226 2021 15 1215 0 |
| allfieldsSound |
10.1016/j.ejmech.2021.113895 doi /cbs_pica/cbs_olc/import_discovery/elsevier/einzuspielen/GBV00000000001663.pica (DE-627)ELV055889166 (ELSEVIER)S0223-5234(21)00744-3 DE-627 ger DE-627 rakwb eng 570 540 VZ BIODIV DE-30 fid 42.00 bkl Sestito, Simona verfasserin aut Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile 2021transfer abstract nicht spezifiziert zzz rdacontent nicht spezifiziert z rdamedia nicht spezifiziert zu rdacarrier We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. Ewing sarcoma Elsevier Dual inhibitors Elsevier Kinases Elsevier Multitarget compounds Elsevier Aurora A Elsevier PDK1 Elsevier Bacci, Andrea oth Chiarugi, Sara oth Runfola, Massimiliano oth Gado, Francesca oth Margheritis, Eleonora oth Gul, Sheraz oth Riveiro, Maria E. oth Vazquez, Ramiro oth Huguet, Samuel oth Manera, Clementina oth Rezai, Keyvan oth Garau, Gianpiero oth Rapposelli, Simona oth Enthalten in Elsevier Science Jose, Ajay ELSEVIER Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles 2018 Amsterdam [u.a.] (DE-627)ELV000457477 volume:226 year:2021 day:15 month:12 pages:0 https://doi.org/10.1016/j.ejmech.2021.113895 Volltext GBV_USEFLAG_U GBV_ELV SYSFLAG_U FID-BIODIV SSG-OLC-PHA 42.00 Biologie: Allgemeines VZ AR 226 2021 15 1215 0 |
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Enthalten in Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles Amsterdam [u.a.] volume:226 year:2021 day:15 month:12 pages:0 |
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Enthalten in Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles Amsterdam [u.a.] volume:226 year:2021 day:15 month:12 pages:0 |
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Sestito, Simona @@aut@@ Bacci, Andrea @@oth@@ Chiarugi, Sara @@oth@@ Runfola, Massimiliano @@oth@@ Gado, Francesca @@oth@@ Margheritis, Eleonora @@oth@@ Gul, Sheraz @@oth@@ Riveiro, Maria E. @@oth@@ Vazquez, Ramiro @@oth@@ Huguet, Samuel @@oth@@ Manera, Clementina @@oth@@ Rezai, Keyvan @@oth@@ Garau, Gianpiero @@oth@@ Rapposelli, Simona @@oth@@ |
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development of potent dual pdk1/aura kinase inhibitors for cancer therapy: lead-optimization, structural insights, and adme-tox profile |
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Development of potent dual PDK1/AurA kinase inhibitors for cancer therapy: Lead-optimization, structural insights, and ADME-Tox profile |
| abstract |
We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. |
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We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. |
| abstract_unstemmed |
We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma. |
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Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.</subfield></datafield><datafield tag="520" ind1=" " ind2=" "><subfield code="a">We report the synthesis of novel first-in-class 2-oxindole-based derivatives as dual PDK1-AurA kinase inhibitors as a novel strategy to treat Ewing sarcoma. The most potent compound 12 is suitable for progression to in vivo studies. The specific attributes of 12 included nanomolar inhibitory potency against both phosphoinositide-dependent kinase-1 (PDK1) and Aurora A (AurA) kinase, with acceptable in vitro ADME-Tox properties (cytotoxicity in 2 healthy and 14 hematological and solid cancer cell-lines; inhibition of PDE4C1, SIRT7, HDAC4, HDAC6, HDAC8, HDAC9, AurB, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and hERG). X-ray crystallography and docking studies led to the identification of the key AurA and PDK1/12 interactions. Finally, in vitro drug-intake kinetics and in vivo PK appear to indicate that these compounds are attractive lead-structures for the design and synthesis of PDK1/AurA dual-target molecules to further investigate the in vivo efficacy against Ewing Sarcoma.</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Ewing sarcoma</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Dual inhibitors</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Kinases</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Multitarget compounds</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">Aurora A</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="650" ind1=" " ind2="7"><subfield code="a">PDK1</subfield><subfield code="2">Elsevier</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Bacci, Andrea</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Chiarugi, Sara</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Runfola, Massimiliano</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Gado, Francesca</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Margheritis, Eleonora</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Gul, Sheraz</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Riveiro, Maria E.</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Vazquez, Ramiro</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Huguet, Samuel</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Manera, Clementina</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rezai, Keyvan</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Garau, Gianpiero</subfield><subfield code="4">oth</subfield></datafield><datafield tag="700" ind1="1" ind2=" "><subfield code="a">Rapposelli, Simona</subfield><subfield code="4">oth</subfield></datafield><datafield tag="773" ind1="0" ind2="8"><subfield code="i">Enthalten in</subfield><subfield code="n">Elsevier Science</subfield><subfield code="a">Jose, Ajay ELSEVIER</subfield><subfield code="t">Electrochemical synthesis, photodegradation and antibacterial properties of PEG capped zinc oxide nanoparticles</subfield><subfield code="d">2018</subfield><subfield code="g">Amsterdam [u.a.]</subfield><subfield code="w">(DE-627)ELV000457477</subfield></datafield><datafield tag="773" ind1="1" ind2="8"><subfield code="g">volume:226</subfield><subfield code="g">year:2021</subfield><subfield code="g">day:15</subfield><subfield code="g">month:12</subfield><subfield code="g">pages:0</subfield></datafield><datafield tag="856" ind1="4" ind2="0"><subfield code="u">https://doi.org/10.1016/j.ejmech.2021.113895</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="912" ind1=" " ind2=" "><subfield code="a">FID-BIODIV</subfield></datafield><datafield tag="912" ind1=" " ind2=" "><subfield code="a">SSG-OLC-PHA</subfield></datafield><datafield tag="936" ind1="b" ind2="k"><subfield code="a">42.00</subfield><subfield code="j">Biologie: Allgemeines</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">226</subfield><subfield code="j">2021</subfield><subfield code="b">15</subfield><subfield code="c">1215</subfield><subfield code="h">0</subfield></datafield></record></collection>
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