5V9T

Crystal structure of selective pyrrolidine amide KDM5a inhibitor N-{(3R)-1-[3-(propan-2-yl)-1H-pyrazole-5-carbonyl]pyrrolidin-3-yl}cyclopropanecarboxamide (compound 48)

5V9T の概要

• エントリーDOI: 10.2210/pdb5v9t/pdb
• 関連するPDBエントリー: 5CEH 5V9P
• 分子名称: Lysine-specific demethylase 5A, NICKEL (II) ION, ZINC ION, ... (6 entities in total)
• 機能のキーワード: histone demethylase, kdm5, kdm5a, epigenetics, cancer, selective, inhibitor, oxidoreductase-oxidoreductase inhibitor complex, oxidoreductase/oxidoreductase inhibitor
• 由来する生物種: Homo sapiens (Human); 詳細
• 細胞内の位置: Nucleus, nucleolus : P29375
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 183236.68

構造登録者

Kiefer, J.R.,Liang, J.,Vinogradova, M. (登録日: 2017-03-23, 公開日: 2017-05-10, 最終更新日: 2024-10-30)

主引用文献

Liang, J.,Labadie, S.,Zhang, B.,Ortwine, D.F.,Patel, S.,Vinogradova, M.,Kiefer, J.R.,Mauer, T.,Gehling, V.S.,Harmange, J.C.,Cummings, R.,Lai, T.,Liao, J.,Zheng, X.,Liu, Y.,Gustafson, A.,Van der Porten, E.,Mao, W.,Liederer, B.M.,Deshmukh, G.,An, L.,Ran, Y.,Classon, M.,Trojer, P.,Dragovich, P.S.,Murray, L.
From a novel HTS hit to potent, selective, and orally bioavailable KDM5 inhibitors.
Bioorg. Med. Chem. Lett., 27:2974-2981, 2017

PubMed Abstract: A high-throughput screening (HTS) of the Genentech/Roche library identified a novel, uncharged scaffold as a KDM5A inhibitor. Lacking insight into the binding mode, initial attempts to improve inhibitor potency failed to improve potency, and synthesis of analogs was further hampered by the presence of a C-C bond between the pyrrolidine and pyridine. Replacing this with a C-N bond significantly simplified synthesis, yielding pyrazole analog 35, of which we obtained a co-crystal structure with KDM5A. Using structure-based design approach, we identified 50 with improved biochemical, cell potency and reduced MW and lower lipophilicity (LogD) compared with the original hit. Furthermore, 50 showed lower clearance than 9 in mice. In combination with its remarkably low plasma protein binding (PPB) in mice (40%), oral dosing of 50 at 5mg/kg resulted in unbound C ∼2-fold of its cell potency (PC9 H3K4Me3 0.96μM), meeting our criteria for an in vivo tool compound from a new scaffold.

PubMed: 28512031
DOI: 10.1016/j.bmcl.2017.05.016

実験手法

X-RAY DIFFRACTION (3.05 Å)