Design, Synthesis, and Pharmacological Evaluation of Isoindoline Analogues as New HPK1 Inhibitors

  • J Med Chem. 2023 Nov 22. doi: 10.1021/acs.jmedchem.3c01571.
Chenghu Xie  1  2 ,  Bo Liu  3  4 ,  Zilan Song  1  2 ,  Ye Yang  3  4 ,  Mengdi Dai  3  4 ,  Yinglei Gao  3  4 ,  Yujia Yao  5 ,  Chunyong Ding  1  2 ,  Jing Ai  3  4 ,  Ao Zhang  1  2  6  5
Affiliations
  • 1. Shanghai Frontiers Science Center of Drug Target Identification and Delivery, School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai 200240, China.
  • 2. National Key Laboratory of Innovative Immunotherapy, Shanghai Jiao Tong University, 800 Dongchuan Road, Minhang District, Shanghai 200240, China.
  • 3. State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China.
  • 6. Lingang Laboratory, Shanghai 200210, China.
PMID: 37990878 DOI: 10.1021/acs.jmedchem.3c01571
Abstract

Hematopoietic progenitor kinase 1 (HPK1) is an important negative regulator in T-cell receptor signaling and as a promising key target for immunotherapy. Herein, based on the reported HPK1 inhibitor 2 featuring an isofuranone component, a structural optimization approach was conducted leading to several series of derivatives characterized by containing an isoindoline structural motif. Compound 49 was identified as a new potent HPK1 inhibitor with an IC50 value of 0.9 nM, more potent than compound 2 (5.5 nM). It also has an improved IV profile in rats and enhanced aqueous solubility. It effectively inhibited pSLP76 and reinvigorated T-cell receptor (TCR) signaling, promoting T-cell function and cytokine production both in naïve and antigen-specific T cells. Furthermore, compound 49 reversed the inhibition on T-cell activity mediated by classic immunosuppressive factors in the tumor microenvironment (TME). In the murine CT-26 tumor model, this compound reinvigorated the T cell and synergistically enhanced the antitumor efficacy of anti-PD1 at a well-tolerant dosage.

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