8XN7
Crystal structure of HPK1 kinase domain T165E,S171E phosphomimetic mutant in complex with compound 9f
This is a non-PDB format compatible entry.
Summary for 8XN7
| Entry DOI | 10.2210/pdb8xn7/pdb |
| Descriptor | 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) |
| Functional Keywords | kinase, transferase |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 2 |
| Total formula weight | 67322.01 |
| Authors | |
| Primary citation | 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 Cited by 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: 38479166DOI: 10.1016/j.ejmech.2024.116310 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.65 Å) |
Structure validation
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