Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp
Animals
Binding Sites
Catalytic Domain
Crystallography, X-Ray
Drug Design
Humans
Imidazoles
/ chemistry
Inhibitory Concentration 50
MAP Kinase Kinase Kinase 5
/ antagonists & inhibitors
Mice
Molecular Dynamics Simulation
Myocardial Reperfusion Injury
/ drug therapy
Protein Kinase Inhibitors
/ chemistry
Apoptosis Signal-Regulating Kinase-1 (ASK1)
Cardiac injury
Kinome selectivity
Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K)
Structure-Based Drug Design (SBDD)
Journal
Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377
Informations de publication
Date de publication:
01 09 2020
01 09 2020
Historique:
received:
19
05
2020
revised:
06
07
2020
accepted:
07
07
2020
entrez:
3
8
2020
pubmed:
3
8
2020
medline:
9
6
2021
Statut:
ppublish
Résumé
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 EC
Identifiants
pubmed: 32738982
pii: S0960-894X(20)30516-3
doi: 10.1016/j.bmcl.2020.127405
pii:
doi:
Substances chimiques
Imidazoles
0
Protein Kinase Inhibitors
0
imidazole
7GBN705NH1
MAP Kinase Kinase Kinase 5
EC 2.7.11.25
MAP3K5 protein, human
EC 2.7.11.25
Types de publication
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
127405Informations de copyright
Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.