Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile.
Bioorg Med Chem Lett, 2020/09/01;30(17):127405.
Bigi-Botterill SV[1], Ivetac A[2], Bradshaw EL[3], Cole D[4], Dougan DR[5], Ermolieff J[4], Halkowycz P[4], Johnson B[6], McBride C[7], Pickens J[4], Sabat M[4], Swann S[8]
Affiliations
PMID: 32738982DOI: 10.1016/j.bmcl.2020.127405
Impact factor: 2.94
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.
Keywords: Apoptosis Signal-Regulating Kinase-1 (ASK1); Cardiac injury; Kinome selectivity; Mitogen-Activated Protein Kinase Kinase Kinase (MAP3K); Structure-Based Drug Design (SBDD)
MeSH terms
Animals; Binding Sites; Catalytic Domain; Crystallography, X-Ray; Drug Design; Humans; Imidazoles; Inhibitory Concentration 50; MAP Kinase Kinase Kinase 5; Mice; Molecular Dynamics Simulation; Myocardial Reperfusion Injury; Protein Kinase Inhibitors
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