2. Academic Validation
  3. Discovery of Novel PROTAC-Based HPK1 Degraders with High Potency and Selectivity for Cancer Immunotherapy

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

Affiliation

  • 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.

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