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

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

  • Eur J Med Chem. 2024 Mar 5:267:116206. doi: 10.1016/j.ejmech.2024.116206.
Shenxin Zeng 1,  Mingfei Wu 2,  Yuyuan Jin 3,  Yingqiao Ye 3,  Heye Xia 3,  Xinyi Chen 3,  Jinxin Che 2,  Zunyuan Wang 3,  Ying Wu 4,  Xiaowu Dong 5,  Yinqiao Chen 6,  Wenhai Huang 7
Affiliations

Affiliations

  • 1 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, PR China. Electronic address: [email protected].
  • 2 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
  • 3 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, PR China.
  • 4 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China.
  • 5 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China. Electronic address: [email protected].
  • 6 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China. Electronic address: [email protected].
  • 7 Affiliated Yongkang First People's Hospital and School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China; Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, School of Pharmacy, Hangzhou Medical College, Hangzhou, Zhejiang, 311399, PR China; Key Discipline of Zhejiang Province in Public Health and Preventive Medicine (First Class, Category A), Hangzhou Medical College, PR China. Electronic address: [email protected].
PMID: 38350360 DOI: 10.1016/j.ejmech.2024.116206
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 IC50 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 (EC50 = 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.

Keywords

Cancer immunotherapy; HPK1; Rigidification strategy; Structure-activity relationship; T-cell immunity.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-157838
    HPK1 Inhibitor