9H8D

Crystal structure of HPK1 T165E/S171E in complex with compound 6

これはPDB形式変換不可エントリーです。

9H8D の概要

• エントリーDOI: 10.2210/pdb9h8d/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 6-(1-methylbenzimidazol-4-yl)-3-[(4-morpholin-4-ylphenyl)amino]pyrazine-2-carboxamide (3 entities in total)
• 機能のキーワード: transferase, kinase, type 1 inhibitor, structure-based drug design
• 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: 33377.70

構造登録者

Schimpl, M.,Pflug, A. (登録日: 2024-10-29, 公開日: 2025-02-19, 最終更新日: 2025-03-05)

主引用文献

Shields, J.D.,Baker, D.,Balazs, A.Y.S.,Bommakanti, G.,Casella, R.,Cao, S.,Cook, S.,Escobar, R.A.,Fawell, S.,Gibbons, F.D.,Giblin, K.A.,Goldberg, F.W.,Gosselin, E.,Grebe, T.,Hariparsad, N.,Hatoum-Mokdad, H.,Howells, R.,Hughes, S.J.,Jackson, A.,Karapa Reddy, I.,Kettle, J.G.,Lamont, G.M.,Lamont, S.,Li, M.,Lill, S.O.N.,Mele, D.A.,Metrano, A.J.,Mfuh, A.M.,Morrill, L.A.,Peng, B.,Pflug, A.,Proia, T.A.,Rezaei, H.,Richards, R.,Richter, M.,Robbins, K.J.,San Martin, M.,Schimpl, M.,Schuller, A.G.,Sha, L.,Shen, M.,Sheppeck 2nd, J.E.,Singh, M.,Stokes, S.,Song, K.,Sun, Y.,Tang, H.,Wagner, D.J.,Wang, J.,Wang, Y.,Wilson, D.M.,Wu, A.,Wu, C.,Wu, D.,Wu, Y.,Xu, K.,Yang, Y.,Yao, T.,Ye, M.,Zhang, A.X.,Zhang, H.,Zhai, X.,Zhou, Y.,Ziegler, R.E.,Grimster, N.P.
Discovery and Optimization of Pyrazine Carboxamide AZ3246, a Selective HPK1 Inhibitor.
J.Med.Chem., 68:4582-4595, 2025

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of the T cell receptor signaling pathway and is therefore a target of interest for immunooncology. Nonselective HPK1 inhibitors may affect other kinase components of T cell activation, blunting the beneficial impact of enhanced T cell activity that results from HPK1 inhibition itself. Here, we report the discovery of pyrazine carboxamide HPK1 inhibitors and their optimization through structure-based drug design to afford a highly selective HPK1 inhibitor, compound (AZ3246). This compound induces IL-2 secretion in T cells with an EC of 90 nM without inhibiting antagonistic kinases, exhibits pharmacokinetic properties consistent with oral dosing, and demonstrates antitumor activity in the EMT6 syngeneic mouse model.

PubMed: 39928839
DOI: 10.1021/acs.jmedchem.4c02631

実験手法

X-RAY DIFFRACTION (1.641 Å)