2. Academic Validation
  3. Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy

Discovery of an Exceptionally Orally Bioavailable and Potent HPK1 PROTAC with Enhancement of Antitumor Efficacy of Anti-PD-L1 Therapy

  • J Med Chem. 2024 Aug 22;67(16):13852-13878. doi: 10.1021/acs.jmedchem.4c00644.
Mingfei Wu 1,  Yiquan Wu 1,  Yuyuan Jin 2,  Xinfei Mao 1,  Shenxin Zeng 2,  Hengyuan Yu 3,  Jingyu Zhang 1,  Yuheng Jin 1,  Yizhe Wu 1,  Tengfei Xu 3,  Yong Chen 3,  Yuwei Wang 4,  Xiaojun Yao 5,  Jinxin Che 1,  Wenhai Huang 2,  Xiaowu Dong 2 6 7
Affiliations

Affiliations

  • 1 Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 2 Key Laboratory of Neuropsychiatric Drug Research of Zhejiang Province, Hangzhou Medical College, Hangzhou 310058, P. R. China.
  • 3 Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, P. R. China.
  • 4 College of Pharmacy, Shaanxi University of Chinese Medicine, Xianyang 712046, P. R. China.
  • 5 Centre for Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macau 999078, P. R. China.
  • 6 Cancer Center, Zhejiang University, Hangzhou 310058, China.
  • 7 Department of Pharmacy, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310009, P. R. China.
PMID: 39084610 DOI: 10.1021/acs.jmedchem.4c00644
Abstract

HPK1, a well-known negative regulator of T cell receptors, can cause T cell dysfunction when abnormally activated. In this study, a PROTAC C3 was designed and synthesized by optimizing the physicochemical properties of the warhead, linker, and CRBN ligand. C3 demonstrated significant HPK1 degradation with a DC50 of 21.26 nM, excellent oral absorption with a Cmax of 10,899.92 ng/mL, and a bioavailability (F %) of 81.7%. C3 also showed degradation selectivity and potent immune activation effects. Proteomic and WB analyses revealed that immune-activating effect of C3 is attributed to the inhibition of SLP76 and NF-κB signaling pathways, as well as the enhancement of MAPK signaling pathway transduction. In vivo efficacy study demonstrated that oral administration of C3 in combination with anti-PDL1 antibody significantly inhibited tumor growth (tumor growth inhibition = 65.58%). These findings suggest that C3, a novel HPK1 PROTAC, holds promise as a therapeutic agent for tumor immunotherapy.

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