Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp

Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in paralle...
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Autor*in:	Bigi-Botterill, Simone V. [verfasserIn] Ivetac, Anthony [verfasserIn] Bradshaw, Erica L. [verfasserIn] Cole, Derek [verfasserIn] Dougan, Douglas R. [verfasserIn] Ermolieff, Jacques [verfasserIn] Halkowycz, Petro [verfasserIn] Johnson, Ben [verfasserIn] McBride, Christopher [verfasserIn] Pickens, Jason [verfasserIn] Sabat, Mark [verfasserIn] Swann, Steven [verfasserIn]

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2020

Schlagwörter:	Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity

Übergeordnetes Werk:	Enthalten in: Bioorganic & medicinal chemistry letters - Amsterdam [u.a.] : Elsevier Science, 1991, 30
Übergeordnetes Werk:	volume:30

DOI / URN:	10.1016/j.bmcl.2020.127405

Katalog-ID:	ELV004442377

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100	1		\|a Bigi-Botterill, Simone V. \|e verfasserin \|4 aut
245	1	0	\|a Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
264		1	\|c 2020
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337			\|a Computermedien \|b c \|2 rdamedia
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520			\|a Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.
650		4	\|a Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K)
650		4	\|a Apoptosis Signal-Regulating Kinase-1 (ASK1)
650		4	\|a Structure-Based Drug Design (SBDD)
650		4	\|a Cardiac injury
650		4	\|a Kinome selectivity
700	1		\|a Ivetac, Anthony \|e verfasserin \|4 aut
700	1		\|a Bradshaw, Erica L. \|e verfasserin \|4 aut
700	1		\|a Cole, Derek \|e verfasserin \|4 aut
700	1		\|a Dougan, Douglas R. \|e verfasserin \|4 aut
700	1		\|a Ermolieff, Jacques \|e verfasserin \|4 aut
700	1		\|a Halkowycz, Petro \|e verfasserin \|4 aut
700	1		\|a Johnson, Ben \|e verfasserin \|4 aut
700	1		\|a McBride, Christopher \|e verfasserin \|4 aut
700	1		\|a Pickens, Jason \|e verfasserin \|4 aut
700	1		\|a Sabat, Mark \|e verfasserin \|4 aut
700	1		\|a Swann, Steven \|e verfasserin \|4 aut
773	0	8	\|i Enthalten in \|t Bioorganic & medicinal chemistry letters \|d Amsterdam [u.a.] : Elsevier Science, 1991 \|g 30 \|h Online-Ressource \|w (DE-627)306717522 \|w (DE-600)1501505-1 \|w (DE-576)110916573 \|x 1464-3405 \|7 nnns
773	1	8	\|g volume:30
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912			\|a GBV_ILN_20
912			\|a GBV_ILN_22
912			\|a GBV_ILN_23
912			\|a GBV_ILN_24
912			\|a GBV_ILN_31
912			\|a GBV_ILN_32
912			\|a GBV_ILN_40
912			\|a GBV_ILN_60
912			\|a GBV_ILN_62
912			\|a GBV_ILN_63
912			\|a GBV_ILN_65
912			\|a GBV_ILN_69
912			\|a GBV_ILN_70
912			\|a GBV_ILN_73
912			\|a GBV_ILN_74
912			\|a GBV_ILN_90
912			\|a GBV_ILN_95
912			\|a GBV_ILN_100
912			\|a GBV_ILN_101
912			\|a GBV_ILN_105
912			\|a GBV_ILN_110
912			\|a GBV_ILN_150
912			\|a GBV_ILN_151
912			\|a GBV_ILN_224
912			\|a GBV_ILN_370
912			\|a GBV_ILN_602
912			\|a GBV_ILN_702
912			\|a GBV_ILN_2003
912			\|a GBV_ILN_2004
912			\|a GBV_ILN_2005
912			\|a GBV_ILN_2011
912			\|a GBV_ILN_2014
912			\|a GBV_ILN_2015
912			\|a GBV_ILN_2020
912			\|a GBV_ILN_2021
912			\|a GBV_ILN_2025
912			\|a GBV_ILN_2027
912			\|a GBV_ILN_2034
912			\|a GBV_ILN_2038
912			\|a GBV_ILN_2044
912			\|a GBV_ILN_2048
912			\|a GBV_ILN_2049
912			\|a GBV_ILN_2050
912			\|a GBV_ILN_2056
912			\|a GBV_ILN_2059
912			\|a GBV_ILN_2061
912			\|a GBV_ILN_2064
912			\|a GBV_ILN_2065
912			\|a GBV_ILN_2068
912			\|a GBV_ILN_2111
912			\|a GBV_ILN_2112
912			\|a GBV_ILN_2113
912			\|a GBV_ILN_2118
912			\|a GBV_ILN_2122
912			\|a GBV_ILN_2129
912			\|a GBV_ILN_2143
912			\|a GBV_ILN_2147
912			\|a GBV_ILN_2148
912			\|a GBV_ILN_2152
912			\|a GBV_ILN_2153
912			\|a GBV_ILN_2190
912			\|a GBV_ILN_2336
912			\|a GBV_ILN_2507
912			\|a GBV_ILN_2522
912			\|a GBV_ILN_4035
912			\|a GBV_ILN_4037
912			\|a GBV_ILN_4112
912			\|a GBV_ILN_4125
912			\|a GBV_ILN_4126
912			\|a GBV_ILN_4242
912			\|a GBV_ILN_4251
912			\|a GBV_ILN_4305
912			\|a GBV_ILN_4313
912			\|a GBV_ILN_4323
912			\|a GBV_ILN_4324
912			\|a GBV_ILN_4326
912			\|a GBV_ILN_4333
912			\|a GBV_ILN_4334
912			\|a GBV_ILN_4335
912			\|a GBV_ILN_4338
912			\|a GBV_ILN_4393
936	b	k	\|a 35.70 \|j Biochemie: Allgemeines
936	b	k	\|a 44.33 \|j Physiologische Chemie
936	b	k	\|a 44.42 \|j Pharmazeutische Chemie
951			\|a AR
952			\|d 30

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publishDate	2020
allfields	10.1016/j.bmcl.2020.127405 doi (DE-627)ELV004442377 (ELSEVIER)S0960-894X(20)30516-3 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Bigi-Botterill, Simone V. verfasserin aut Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity Ivetac, Anthony verfasserin aut Bradshaw, Erica L. verfasserin aut Cole, Derek verfasserin aut Dougan, Douglas R. verfasserin aut Ermolieff, Jacques verfasserin aut Halkowycz, Petro verfasserin aut Johnson, Ben verfasserin aut McBride, Christopher verfasserin aut Pickens, Jason verfasserin aut Sabat, Mark verfasserin aut Swann, Steven verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 30 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:30 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 30
spelling	10.1016/j.bmcl.2020.127405 doi (DE-627)ELV004442377 (ELSEVIER)S0960-894X(20)30516-3 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Bigi-Botterill, Simone V. verfasserin aut Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity Ivetac, Anthony verfasserin aut Bradshaw, Erica L. verfasserin aut Cole, Derek verfasserin aut Dougan, Douglas R. verfasserin aut Ermolieff, Jacques verfasserin aut Halkowycz, Petro verfasserin aut Johnson, Ben verfasserin aut McBride, Christopher verfasserin aut Pickens, Jason verfasserin aut Sabat, Mark verfasserin aut Swann, Steven verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 30 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:30 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 30
allfields_unstemmed	10.1016/j.bmcl.2020.127405 doi (DE-627)ELV004442377 (ELSEVIER)S0960-894X(20)30516-3 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Bigi-Botterill, Simone V. verfasserin aut Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity Ivetac, Anthony verfasserin aut Bradshaw, Erica L. verfasserin aut Cole, Derek verfasserin aut Dougan, Douglas R. verfasserin aut Ermolieff, Jacques verfasserin aut Halkowycz, Petro verfasserin aut Johnson, Ben verfasserin aut McBride, Christopher verfasserin aut Pickens, Jason verfasserin aut Sabat, Mark verfasserin aut Swann, Steven verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 30 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:30 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 30
allfieldsGer	10.1016/j.bmcl.2020.127405 doi (DE-627)ELV004442377 (ELSEVIER)S0960-894X(20)30516-3 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Bigi-Botterill, Simone V. verfasserin aut Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity Ivetac, Anthony verfasserin aut Bradshaw, Erica L. verfasserin aut Cole, Derek verfasserin aut Dougan, Douglas R. verfasserin aut Ermolieff, Jacques verfasserin aut Halkowycz, Petro verfasserin aut Johnson, Ben verfasserin aut McBride, Christopher verfasserin aut Pickens, Jason verfasserin aut Sabat, Mark verfasserin aut Swann, Steven verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 30 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:30 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 30
allfieldsSound	10.1016/j.bmcl.2020.127405 doi (DE-627)ELV004442377 (ELSEVIER)S0960-894X(20)30516-3 DE-627 ger DE-627 rda eng 540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Bigi-Botterill, Simone V. verfasserin aut Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp 2020 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series. Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity Ivetac, Anthony verfasserin aut Bradshaw, Erica L. verfasserin aut Cole, Derek verfasserin aut Dougan, Douglas R. verfasserin aut Ermolieff, Jacques verfasserin aut Halkowycz, Petro verfasserin aut Johnson, Ben verfasserin aut McBride, Christopher verfasserin aut Pickens, Jason verfasserin aut Sabat, Mark verfasserin aut Swann, Steven verfasserin aut Enthalten in Bioorganic & medicinal chemistry letters Amsterdam [u.a.] : Elsevier Science, 1991 30 Online-Ressource (DE-627)306717522 (DE-600)1501505-1 (DE-576)110916573 1464-3405 nnns volume:30 GBV_USEFLAG_U SYSFLAG_U GBV_ELV FID-PHARM SSG-OLC-PHA SSG-OPC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_150 GBV_ILN_151 GBV_ILN_224 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2003 GBV_ILN_2004 GBV_ILN_2005 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2038 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2065 GBV_ILN_2068 GBV_ILN_2111 GBV_ILN_2112 GBV_ILN_2113 GBV_ILN_2118 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2147 GBV_ILN_2148 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2336 GBV_ILN_2507 GBV_ILN_2522 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4313 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4335 GBV_ILN_4338 GBV_ILN_4393 35.70 Biochemie: Allgemeines 44.33 Physiologische Chemie 44.42 Pharmazeutische Chemie AR 30
language	English
source	Enthalten in Bioorganic & medicinal chemistry letters 30 volume:30
sourceStr	Enthalten in Bioorganic & medicinal chemistry letters 30 volume:30
format_phy_str_mv	Article
bklname	Biochemie: Allgemeines Physiologische Chemie Pharmazeutische Chemie
institution	findex.gbv.de
topic_facet	Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity
dewey-raw	540
isfreeaccess_bool	false
container_title	Bioorganic & medicinal chemistry letters
authorswithroles_txt_mv	Bigi-Botterill, Simone V. @@aut@@ Ivetac, Anthony @@aut@@ Bradshaw, Erica L. @@aut@@ Cole, Derek @@aut@@ Dougan, Douglas R. @@aut@@ Ermolieff, Jacques @@aut@@ Halkowycz, Petro @@aut@@ Johnson, Ben @@aut@@ McBride, Christopher @@aut@@ Pickens, Jason @@aut@@ Sabat, Mark @@aut@@ Swann, Steven @@aut@@
publishDateDaySort_date	2020-01-01T00:00:00Z
hierarchy_top_id	306717522
dewey-sort	3540
id	ELV004442377
language_de	englisch
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author	Bigi-Botterill, Simone V.
spellingShingle	Bigi-Botterill, Simone V. ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) misc Apoptosis Signal-Regulating Kinase-1 (ASK1) misc Structure-Based Drug Design (SBDD) misc Cardiac injury misc Kinome selectivity Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
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topic_title	540 610 DE-600 15,3 ssgn PHARM DE-84 fid 35.70 bkl 44.33 bkl 44.42 bkl Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) Apoptosis Signal-Regulating Kinase-1 (ASK1) Structure-Based Drug Design (SBDD) Cardiac injury Kinome selectivity
topic	ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) misc Apoptosis Signal-Regulating Kinase-1 (ASK1) misc Structure-Based Drug Design (SBDD) misc Cardiac injury misc Kinome selectivity
topic_unstemmed	ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) misc Apoptosis Signal-Regulating Kinase-1 (ASK1) misc Structure-Based Drug Design (SBDD) misc Cardiac injury misc Kinome selectivity
topic_browse	ddc 540 ssgn 15,3 fid PHARM bkl 35.70 bkl 44.33 bkl 44.42 misc Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) misc Apoptosis Signal-Regulating Kinase-1 (ASK1) misc Structure-Based Drug Design (SBDD) misc Cardiac injury misc Kinome selectivity
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title	Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
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title_full	Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
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author_browse	Bigi-Botterill, Simone V. Ivetac, Anthony Bradshaw, Erica L. Cole, Derek Dougan, Douglas R. Ermolieff, Jacques Halkowycz, Petro Johnson, Ben McBride, Christopher Pickens, Jason Sabat, Mark Swann, Steven
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title_sort	structure-guided optimization of a novel class of ask1 inhibitors with increased sp
title_auth	Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
abstract	Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.
abstractGer	Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.
abstract_unstemmed	Apoptosis Signal-Regulating Kinase-1 (ASK1) is a known member of the Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K) family and upon stimulation will activate the p38- and JNK-pathways leading to cardiac apoptosis, fibrosis, and hypertrophy. Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. Based on crystallographic data, the presence of an aliphatic cycle adjacent to the hinge-binder in the active site of the protein kinase showed up in <1% of the >5000 structures in the Protein Data Bank, potentially conferring the selectivity seen in this series.
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title_short	Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
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author2	Ivetac, Anthony Bradshaw, Erica L. Cole, Derek Dougan, Douglas R. Ermolieff, Jacques Halkowycz, Petro Johnson, Ben McBride, Christopher Pickens, Jason Sabat, Mark Swann, Steven
author2Str	Ivetac, Anthony Bradshaw, Erica L. Cole, Derek Dougan, Douglas R. Ermolieff, Jacques Halkowycz, Petro Johnson, Ben McBride, Christopher Pickens, Jason Sabat, Mark Swann, Steven
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doi_str	10.1016/j.bmcl.2020.127405
up_date	2024-07-06T23:00:17.313Z
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Using Structure-Based Drug Design (SBDD) in parallel with deconstruction of a published compound, a novel series of ASK1 inhibitors was optimized, which incorporated a saturated heterocycle proximal to the hinge-binding motif. This yielded a unique chemical series with excellent selectivity across the broader kinome, and desirable drug-like properties. The lead compound (10) is highly soluble and permeable, and exhibits a cellular EC50 = 24 nM and Kd < 1 nM. Of the 350 kinases tested, 10 has an IC50 ≤ 500 nM for only eight of them. This paper will describe the design hypotheses behind this series, key data points during the optimization phase, as well as a possible structural rationale for the kinome selectivity. 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Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp

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