7PUS

ERK5 in complex with Pyrrole Carboxamide scaffold

これはPDB形式変換不可エントリーです。

7PUS の概要

• エントリーDOI: 10.2210/pdb7pus/pdb
• 関連するPDBエントリー: 5O7I
• 分子名称: Mitogen-activated protein kinase 7, 4-[3,6-bis(chloranyl)-2-fluoranyl-phenyl]carbonyl-~{N}-(1-methylpyrazol-4-yl)-1~{H}-pyrrole-2-carboxamide (3 entities in total)
• 機能のキーワード: kinase, inhibitor, pyrrole, transferase
• 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: 41438.42

構造登録者

Tucker, J.A.,Martin, M.P.,Endicott, J.A.,Noble, M.E.N. (登録日: 2021-09-30, 公開日: 2022-05-11, 最終更新日: 2024-01-31)

主引用文献

Miller, D.C.,Reuillon, T.,Molyneux, L.,Blackburn, T.,Cook, S.J.,Edwards, N.,Endicott, J.A.,Golding, B.T.,Griffin, R.J.,Hardcastle, I.,Harnor, S.J.,Heptinstall, A.,Lochhead, P.,Martin, M.P.,Martin, N.C.,Myers, S.,Newell, D.R.,Noble, R.A.,Phillips, N.,Rigoreau, L.,Thomas, H.,Tucker, J.A.,Wang, L.Z.,Waring, M.J.,Wong, A.C.,Wedge, S.R.,Noble, M.E.M.,Cano, C.
Parallel Optimization of Potency and Pharmacokinetics Leading to the Discovery of a Pyrrole Carboxamide ERK5 Kinase Domain Inhibitor.
J.Med.Chem., 65:6513-6540, 2022

PubMed Abstract: The nonclassical extracellular signal-related kinase 5 (ERK5) mitogen-activated protein kinase pathway has been implicated in increased cellular proliferation, migration, survival, and angiogenesis; hence, ERK5 inhibition may be an attractive approach for cancer treatment. However, the development of selective ERK5 inhibitors has been challenging. Previously, we described the development of a pyrrole carboxamide high-throughput screening hit into a selective, submicromolar inhibitor of ERK5 kinase activity. Improvement in the ERK5 potency was necessary for the identification of a tool ERK5 inhibitor for target validation studies. Herein, we describe the optimization of this series to identify nanomolar pyrrole carboxamide inhibitors of ERK5 incorporating a basic center, which suffered from poor oral bioavailability. Parallel optimization of potency and pharmacokinetic parameters led to the identification of a nonbasic pyrazole analogue with an optimal balance of ERK5 inhibition and oral exposure.

PubMed: 35468293
DOI: 10.1021/acs.jmedchem.1c01756

実験手法

X-RAY DIFFRACTION (2.59 Å)