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. 2023 Sep 7:92:117423.
doi: 10.1016/j.bmc.2023.117423. Epub 2023 Jul 27.

Discovery of quinazoline HPK1 inhibitors with high cellular potency

Momar Toure  1 , Theresa Johnson  2 , Bin Li  2 , Ralf Schmidt  2 , Hong Ma  2 , Constantin Neagu  2 , Andrea Unzue Lopez  2 , Yanping Wang  2 , Satenig Guler  2 , YuFang Xiao  2 , Renate Henkes  2 , Kevin Ho  2 , Susan Zhang  2 , Chia Lin Chu  2 , Uma Mahesh Gundra  2 , Filippos Porichis  2 , Long Li  2 , Christine Katharina Maurer  2 , Zhizhou Fang  2 , Djordje Musil  2 , Maria DiPoto  2 , Emily Friis  2 , Reinaldo Jones  2 , Christopher Jones  2 , James Cummings  2 , Eugene Chekler  2 , Eva Maria Tanzer  2 , Bayard Huck  2 , Brian Sherer  2
Affiliations

Discovery of quinazoline HPK1 inhibitors with high cellular potency

Momar Toure et al. Bioorg Med Chem. .

Abstract

Hematopoietic progenitor kinase 1 (HPK1) is regarded as a highly validated target in pre-clinical immune oncology. HPK1 has been described as regulating multiple critical signaling pathway in both adaptive and innate cells. In support of this role, HPK1 KO T cells show enhanced sensitivity to TCR activation and HPK1 KO mice display enhanced anti-tumor activity. Taken together, inhibition of HPK1 has the potential to induce enhanced anti-tumor immune response. Herein, we described the discovery of highly potent HPK1 inhibitors starting form a weak HTS hit. Using a structure-based drug design, HPK1 inhibitors exhibiting excellent cellular single-digit nanomolar potency in both proximal (pSLP76) and distal (IL-2) biomarkers along with sustained elevation of IL-2 cytokine secretion were discovered.

Keywords: HPK1; Inhibitors; Kinase; Optimization; Quinazoline; pSLP76.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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