8XN7

Crystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 9f

これはPDB形式変換不可エントリーです。

8XN7 の概要

• エントリーDOI: 10.2210/pdb8xn7/pdb
• 分子名称: Mitogen-activated protein kinase kinase kinase kinase 1, 5-amino-2-((6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-8-(2-(trifluoromethyl)benzyl)pyrido[2,3-d]pyrimidin-7(8H)-one (3 entities in total)
• 機能のキーワード: kinase, transferase
• 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: 67322.01

構造登録者

Huang, W.X.,Liu, R.,Ding, K. (登録日: 2023-12-29, 公開日: 2024-04-10)

主引用文献

Qiu, X.,Liu, R.,Ling, H.,Zhou, Y.,Ren, X.,Zhou, F.,Zhang, J.,Huang, W.,Wang, Z.,Ding, K.
Discovery of 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors.
Eur.J.Med.Chem., 269:116310-116310, 2024

PubMed Abstract: Hematopoietic progenitor kinase 1 (HPK1) is a negative regulator of T-cell receptor signaling. While HPK1 is considered as a promising target for cancer immunotherapy, no small-molecule HPK1 inhibitors have been approved for cancer treatment. Herein, we report the discovery of a series of new HPK1 inhibitors with a 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one scaffold. The most potent compound 9f inhibited HPK1 kinase activity with an IC of 0.32 nM in the time-resolved fluorescence resonance energy transfer (TR-FRET) assays, while displayed reasonable selectivity in a panel of 416 kinases. Cellular engagement of HPK1 by compound 9f was confirmed through the nano-bioluminescence resonance energy transfer (Nano-BRET) experiments. Compound 9f effectively reduced the phosphorylation of the downstream protein SLP-76 in primary peripheral blood mononuclear cells (PBMCs) and human T lymphocytic leukemia Jurkat cells. Compound 9f also enhanced the IL-2 and IFN-γ secretion in PBMCs. Furthermore, the binding mode of compound 9f with HPK1 was confirmed by the resolved cocrystal structure. Taken together, this study provides HPK1 inhibitors with a novel scaffold and clear binding mode for further development of HPK1-targeted therapeutic agents.

PubMed: 38479166
DOI: 10.1016/j.ejmech.2024.116310

実験手法

X-RAY DIFFRACTION (2.65 Å)