6XIH

Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3 character and an exquisite selectivity profile

6XIH の概要

• エントリーDOI: 10.2210/pdb6xih/pdb
• 関連するPDBエントリー: 5UP3
• 分子名称: Mitogen-activated protein kinase kinase kinase 5, (2R)-N-{6-[4-(propan-2-yl)-4H-1,2,4-triazol-3-yl]pyridin-2-yl}oxane-2-carboxamide (3 entities in total)
• 機能のキーワード: transferase, metal-binding, apoptosis, serine/threonine kinase, metal binding protein
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 67242.81

構造登録者

Dougan, D.R. (登録日: 2020-06-19, 公開日: 2020-08-12, 最終更新日: 2023-10-18)

主引用文献

Bigi-Botterill, S.V.,Ivetac, A.,Bradshaw, E.L.,Cole, D.,Dougan, D.R.,Ermolieff, J.,Halkowycz, P.,Johnson, B.,McBride, C.,Pickens, J.,Sabat, M.,Swann, S.
Structure-guided optimization of a novel class of ASK1 inhibitors with increased sp3character and an exquisite selectivity profile.
Bioorg.Med.Chem.Lett., 30:127405-127405, 2020

PubMed 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 EC = 24 nM and K < 1 nM. Of the 350 kinases tested, 10 has an IC ≤ 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.

PubMed: 32738982
DOI: 10.1016/j.bmcl.2020.127405

実験手法

X-RAY DIFFRACTION (2.65 Å)