Discovery of Novel Src Homology-2 Domain-Containing Phosphatase 2 and Histone Deacetylase Dual Inhibitors with Potent Antitumor Efficacy and Enhanced Antitumor Immunity

J Med Chem. 2022 Sep 22;65(18):12200-12218. doi: 10.1021/acs.jmedchem.2c00866. Epub 2022 Sep 12.

Abstract

Both Src homology-2 domain-containing phosphatase 2 (SHP2) and histone deacetylase (HDAC) are important oncoproteins and potential immunomodulators. In this study, we first observed a synergistic antiproliferation effect of an allosteric SHP2 inhibitor (SHP099) and HDAC inhibitor (SAHA) in MV4-11 cells. Inspired by this result, a series of SHP2/HDAC dual inhibitors were designed based on the pharmacophore fusion strategy. Among these inhibitors, the most potent compound 8t showed excellent inhibitory activities against SHP2 (IC50 = 20.4 nM) and HDAC1 (IC50 = 25.3 nM). In particular, compound 8t exhibited improved antitumor activities compared with those of SHP099 and SAHA in vitro and in vivo. Our study also indicated that treatment with 8t could trigger efficient antitumor immunity by activating T cells, enhancing the antigen presentation function and promoting cytokine secretion. To our knowledge, we report the first small molecular SHP2/HDAC dual inhibitor and demonstrate a new strategy for cancer immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents* / pharmacology
  • Antineoplastic Agents* / therapeutic use
  • Cell Line, Tumor
  • Cell Proliferation
  • Cytokines / pharmacology
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors* / pharmacology
  • Histone Deacetylase Inhibitors* / therapeutic use
  • Histone Deacetylases / metabolism
  • Humans
  • Phosphoric Monoester Hydrolases
  • Piperidines
  • Pyrimidines
  • Vorinostat

Substances

  • Antineoplastic Agents
  • Cytokines
  • Histone Deacetylase Inhibitors
  • Piperidines
  • Pyrimidines
  • SHP099
  • Vorinostat
  • Phosphoric Monoester Hydrolases
  • Histone Deacetylases