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

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.