9BJ1

Crystal structure of inhibitor GNE-6893 bound to HPK1

これはPDB形式変換不可エントリーです。

9BJ1 の概要

• エントリーDOI: 10.2210/pdb9bj1/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, 1,2-ETHANEDIOL, ... (9 entities in total)
• 機能のキーワード: hpk1, map4k1, cancer, pharmacology, kinase, inhibitor, signaling protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 72176.37

構造登録者

Kiefer, J.R.,Tellis, J.C.,Chan, B.K.,Wang, W.,Wu, P.,Choo, E.F.,Heffron, T.P.,Wei, B.,Siu, M. (登録日: 2024-04-24, 公開日: 2024-10-02)

主引用文献

Tellis, J.C.,Wei, B.,Siu, M.,An, L.,Chan, G.K.,Chen, Y.,Du, X.,Gazzard, L.,Hu, B.,Kiefer, J.,Kakiuchi-Kiyota, S.,Lainchbury, M.,Linehan, J.L.,Luo, X.,Malhotra, S.,Mendonca, R.,Pang, J.,Ran, Y.,Sethuraman, V.,Seward, E.,Sneeringer, C.,Su, D.,Wang, W.,Wu, P.,Moffat, J.G.,Heffron, T.P.,Choo, E.F.,Chan, B.K.
Discovery of GNE-6893, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of HPK1.
Acs Med.Chem.Lett., 15:1606-1614, 2024

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) serves a key immunosuppressive role as a negative regulator of T-cell receptor (TCR) signaling. HPK1 loss-of-function is associated with augmentation of immune function and has demonstrated synergy with immune checkpoint inhibitors in syngeneic mouse cancer models. These data offer compelling evidence for the use of selective small molecule inhibitors of HPK1 in cancer immunotherapy. We identified a novel series of isoquinoline HPK1 inhibitors through fragment-based screening that displayed promising levels of biochemical potency and activity in functional cell-based assays. We used structure-based drug design to introduce key selectivity elements while simultaneously addressing pharmacokinetic liabilities. These efforts culminated in a molecule demonstrating subnanomolar biochemical inhibition of HPK1 and strong augmentation of TCR signaling in primary human T-cells. Further profiling of this molecule revealed excellent kinase selectivity (347/356 kinases <50% inhibition @ 0.1 μM), a favorable safety profile, and good projected human pharmacokinetics.

PubMed: 39291002
DOI: 10.1021/acsmedchemlett.4c00319

実験手法

X-RAY DIFFRACTION (2.18 Å)