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
  • 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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