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

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

Eur J Med Chem

State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd., Shanghai, 200032, China; International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China; Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang, 310022, China. Electronic address:

Published: April 2024

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.

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Source
http://dx.doi.org/10.1016/j.ejmech.2024.116310DOI Listing

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