6PDD

Crystal structure of MYST acetyltransferase domain in complex with inhibitor 41

6PDD の概要

• エントリーDOI: 10.2210/pdb6pdd/pdb
• 分子名称: Histone acetyltransferase KAT8, ZINC ION, SODIUM ION, ... (7 entities in total)
• 機能のキーワード: inhibitor, complex, myst, transferase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32676.85

構造登録者

Hermans, S.J.,Parker, M.W.,Thomas, T.,Baell, J.B. (登録日: 2019-06-18, 公開日: 2020-04-01, 最終更新日: 2024-11-20)

主引用文献

Priebbenow, D.L.,Leaver, D.J.,Nguyen, N.,Cleary, B.,Lagiakos, H.R.,Sanchez, J.,Xue, L.,Huang, F.,Sun, Y.,Mujumdar, P.,Mudududdla, R.,Varghese, S.,Teguh, S.,Charman, S.A.,White, K.L.,Shackleford, D.M.,Katneni, K.,Cuellar, M.,Strasser, J.M.,Dahlin, J.L.,Walters, M.A.,Street, I.P.,Monahan, B.J.,Jarman, K.E.,Jousset Sabroux, H.,Falk, H.,Chung, M.C.,Hermans, S.J.,Downer, N.L.,Parker, M.W.,Voss, A.K.,Thomas, T.,Baell, J.B.
Discovery of Acylsulfonohydrazide-Derived Inhibitors of the Lysine Acetyltransferase, KAT6A, as Potent Senescence-Inducing Anti-Cancer Agents.
J.Med.Chem., 63:4655-4684, 2020

PubMed Abstract: A high-throughput screen designed to discover new inhibitors of histone acetyltransferase KAT6A uncovered CTX-0124143 (), a unique aryl acylsulfonohydrazide with an IC of 1.0 μM. Using this acylsulfonohydrazide as a template, we herein disclose the results of our extensive structure-activity relationship investigations, which resulted in the discovery of advanced compounds such as and . These two compounds represent significant improvements on our recently reported prototypical lead WM-8014 () as they are not only equivalently potent as inhibitors of KAT6A but are less lipophilic and significantly more stable to microsomal degradation. Furthermore, during this process, we discovered a distinct structural subclass that contains key 2-fluorobenzenesulfonyl and phenylpyridine motifs, culminating in the discovery of WM-1119 (). This compound is a highly potent KAT6A inhibitor (IC = 6.3 nM; = 0.002 μM), competes with Ac-CoA by binding to the Ac-CoA binding site, and has an oral bioavailability of 56% in rats.

PubMed: 32118427
DOI: 10.1021/acs.jmedchem.9b02071

実験手法

X-RAY DIFFRACTION (2.15 Å)