Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy

  • J Med Chem. 2024 Nov 14;67(21):18682-18698. doi: 10.1021/acs.jmedchem.4c01906.
Zhimin Zhang  1 ,  Liubin Guo  1 ,  Mengting Zhao  1 ,  Hao Pan  1 ,  Zhao Dong  1 ,  Ling Wang  1 ,  Xi Yang  1 ,  Zhiping Zhang  1 ,  Mengqiang Wu  1 ,  Yujie Chang  1 ,  Yacheng Yang  1 ,  Linan Sun  1 ,  Sirui Liu  1 ,  Rongyao Zhu  1 ,  Haowen Zheng  1 ,  Xinyu Dai  1 ,  Xiaohua Zhang  1 ,  Chunhua Jiang  1 ,  Zhuangzhi Zhu  1 ,  Yuchen Zhang  1 ,  Dongzhou Liu  1
Affiliations
  • 1. Global Drug R&D Center, Huadong Medicine, Hangzhou 310011, P. R. China.
PMID: 39446986 DOI: 10.1021/acs.jmedchem.4c01906
Abstract

Hematopoietic progenitor kinase 1 (HPK1, MAP4K1), a serine/threonine (SER/THR) kinase, has been identified as a negative immune regulator of T-cell receptor signaling. Deprivation of the HPK1 function suppresses tumor growth, providing an attractive strategy for Cancer Immunotherapy. Herein, we present a novel PROTAC-based HPK1 degrader compound DD205-291 with high selectivity and potency. DD205-291 showed a dose-dependent inhibition of SLP-76 phosphorylation and an induction of IL-2 and IFN-γ. Compared with Other inhibitors, DD205-291 exhibited good efficacy and a favorable safety profile in the MC38 model. Specifically, oral administration of DD205-291 at 0.5 mg/kg in combination with anti-PD1 resulted in significant suppression with a TGI value of 91.0%. Furthermore, DD205-291 exhibited a low risk of cardiotoxicity and a wide safety window. This research effort demonstrates that DD205-291 is a promising preclinical candidate (PCC) for potential mono- and comboimmunotherapy of Cancer.

Products