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Discovery of novel, potent, selective and orally bioavailable HPK1 inhibitor for enhancing the efficacy of anti-PD-L1 antibody.

Authors :
Zeng, Shenxin
Wu, Mingfei
Jin, Yuyuan
Ye, Yingqiao
Xia, Heye
Chen, Xinyi
Che, Jinxin
Wang, Zunyuan
Wu, Ying
Dong, Xiaowu
Chen, Yinqiao
Huang, Wenhai
Source :
European Journal of Medicinal Chemistry. Mar2024, Vol. 267, pN.PAG-N.PAG. 1p.
Publication Year :
2024

Abstract

Hematopoietic progenitor kinase 1 (HPK1), a serine/threonine kinase in the MAP4K family, is expressed predominantly in immune cells, and has been identified as a negative regulator of immune signaling. Accumulating evidences demonstrated that loss of HPK1 kinase function effectively enhances anti-tumor responses. In this study, we disclose the medicinal chemistry campaigns to discovery potent, selective, and orally active HPK1 inhibitors, starting from our previous work based on rigidification strategy. Systematically structure-activity relationship (SAR) exploration led to the identification of F03 (HMC-B17). The representative compound, HMC-B17 , showed the potent HPK1 inhibition with an IC 50 value of 1.39 nM and favorable selectivity against TCR-related kinases. In addition, the HMC-B17 effectively enhanced the IL-2 secretion in Jurkat cells (EC 50 = 11.56 nM). Strikingly, immune-reverse effects and improved immune response in vivo were observed after HMC-B17 treatment. Furthermore, HMC-B17 combined with anti -PD-L1 antibody demonstrated a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model. Collectively, our findings suggest that HMC-B17 could be a valuable lead compound to develop a safe and potent HPK1 inhibitor for further cancer immunotherapy. [Display omitted] • Highly TCR-related kinases selectivity is critical for the success of HPK1 drug discovery. • In this study, systematically SAR explorations were performed, and compound HMC-B17 was identified as a novel, potent, selective and orally bioavailable HPK1 inhibitor. • HMC-B17 showed a synergistic antitumor efficacy with TGI% value of 71.24 % in CT26 model when combined with anti -PD-L1 antibody. • Compound HMC-B17 is a promising chemical entity, which deserves further investigation in cancer immunotherapy filed. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
02235234
Volume :
267
Database :
Academic Search Index
Journal :
European Journal of Medicinal Chemistry
Publication Type :
Academic Journal
Accession number :
175569479
Full Text :
https://doi.org/10.1016/j.ejmech.2024.116206