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Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion. | LitMetric

Discovery of potent and selective HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold with immune modulatory properties for ameliorating T cell exhaustion.

Bioorg Chem

Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang 311399, China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College. Electronic address:

Published: October 2023

Hematopoietic progenitor kinase 1 (HPK1), a member of the mitogen-activated protein kinase (MAP4K) family, is a serine/threonine (SER/THR) kinase and has been demonstrated as a negative regulator of T cell receptor signaling. Targeting HPK1 has been considered as an attractive therapeutic strategy for immune-oncology. Here, we describe the discovery and structure-activity relationship (SAR) of potent HPK1 inhibitors based on the 2,4-disubstituted pyrimidine scaffold. Systematically SAR exploration afforded the desired compound HMC-H8 (F1) with potent HPK1 inhibition (IC = 1.11 nM) and highly selectivity profile. Compound HMC-H8 also exhibited robust inhibition of p-SLP 76 (IC = 283.0 nM) and promotion IL-2 release (EC = 157.08 nM), and INF-γ production in a dose-dependent manner in vitro assays. Strikingly, HMC-H8 shown effective immune reversal response in immunesuppressive condition. Moreover, Compound HMC-H8 displayed acceptable metabolic stability (T = 56.87 min), along with low CYP450 inhibition in human liver microsomes and good oral bioavailability (F = 15.05%) in rat. Furthermore, HMC-H8 was found to modulate the expression of c-Myc in Western blotting experiments. Taken together, this study provides new potent HPK1 inhibitors for further anticancer drug discovery based on immuno-oncology.

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http://dx.doi.org/10.1016/j.bioorg.2023.106728DOI Listing

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