Design, synthesis, and biological evaluation of novel HPK1 inhibitors possessing 3-cyano-quinoline moiety

Long Chen; Baixue Zhang; Pijun Zhou; Yiping Duan; Chen He; Wenyi Zhong; Tianyi Wang; Shengtao Xu; Jichao Chen; Hong Yao; Jinyi Xu

doi:10.1016/j.bioorg.2024.107814

Design, synthesis, and biological evaluation of novel HPK1 inhibitors possessing 3-cyano-quinoline moiety

Bioorg Chem. 2024 Sep 12:153:107814. doi: 10.1016/j.bioorg.2024.107814. Online ahead of print.

Authors

Long Chen¹, Baixue Zhang¹, Pijun Zhou¹, Yiping Duan¹, Chen He¹, Wenyi Zhong¹, Tianyi Wang¹, Shengtao Xu¹, Jichao Chen², Hong Yao³, Jinyi Xu⁴

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
² School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, PR China. Electronic address: chenjichao@njucm.edu.cn.
³ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: hyao1989@sina.cn.
⁴ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.

PMID: 39299176
DOI: 10.1016/j.bioorg.2024.107814

Abstract

Hematopoietic progenitor kinase 1 (HPK1), a negative regulator of T cell receptor signaling, plays a crucial role in multiple cellular immune responses. Emerging researches have demonstrated that inhibiting HPK1 kinase function enhances T cells' ability to recognize tumor antigens and boosts anti-tumor immune responses. As a result, HPK1 has become a promising target for tumor immunotherapy. Herein, we report the design, synthesis, and biological evaluation of a series of novel HPK1 inhibitors featuring a 3-cyano-quinoline scaffold. Among these, compound 3a was identified as the most potent HPK1 inhibitor (HPK1 IC₅₀ = 48 nM). It effectively inhibited SLP76 phosphorylation, enhanced IL-2 cytokine secretion, and reversed PGE2-induced immunosuppression in Jurkat cells. In addition, compound 3a exhibited favorable metabolic stability in mouse liver microsomes and plasma. Overall, this work provides a structurally novel lead compound for the development of HPK1 inhibitors.

Keywords: 3-Cyano-quinoline; Cancer immunotherapy; HPK1 inhibitors; Immunosuppression.