Discovery of 5-aminopyrido[2,3-d]pyrimidin-7(8H)-one derivatives as new hematopoietic progenitor kinase 1 (HPK1) inhibitors

Eur J Med Chem. 2024 Mar 5;269:116310. doi: 10.1016/j.ejmech.2024.116310. Online ahead of print.ABSTRACTHematopoietic 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 IC50 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.PMID:38479166 | DOI:10.1016/j.ejmech.2024.116310
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research