9QT6

Crystal structure of HPK1 T165E/S171E in complex with pyrazine carboxamide inhibitor

これはPDB形式変換不可エントリーです。

9QT6 の概要

• エントリーDOI: 10.2210/pdb9qt6/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 3-[(1,3-dimethylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: 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: 33402.71

構造登録者

Schimpl, M. (登録日: 2025-04-08, 公開日: 2025-05-28, 最終更新日: 2025-09-03)

主引用文献

Metrano, A.J.,Morrill, L.A.,Bommakanti, G.,Casella, R.,Cook, S.,Escobar, R.A.,Giblin, K.A.,Gosselin, E.,Grebe, T.,Hariparsad, N.,Howells, R.,Lamont, G.M.,Mele, D.A.,Pflug, A.,Proia, T.A.,Rezaei, H.,Richter, M.,Richards, R.,San Martin, M.,Schimpl, M.,Schuller, A.G.,Sha, L.,Sheppeck 2nd, J.E.,Song, K.,Tang, H.,Wagner, D.J.,Wang, J.,Wu, A.,Wu, D.,Wu, Y.,Xu, K.,Ye, M.,Shields, J.D.,Grimster, N.P.
Synthetic chemistry enabling the discovery and development of a series of pyrazoles as HPK1 inhibitors.
Rsc Med Chem, 16:3522-3529, 2025

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell signaling. Inhibition of HPK1 with small molecules has been shown to reinvigorate the immune system toward fighting tumours in preclinical models, thus it holds promise as a therapeutic strategy in cancer immunotherapy. Herein we report a series of pyrazine carboxamide pyrazoles as selective inhibitors of HPK1. Key to our approach was the development of late-stage functionalisation chemistry which allowed for rapid SAR generation. Through these efforts, we discovered difluoroethyl pyrazole 16a, an tool which elicited the desired pharmacodynamic response in mice. Further, we describe the optimization of synthetic chemistry which could support preclinical studies of a member of this series of substituted pyrazoles.

PubMed: 40521343
DOI: 10.1039/d5md00309a

実験手法

X-RAY DIFFRACTION (1.76 Å)