Recently, Professor Fang Hao and Associate Professor Hou Xuben from the School of Pharmaceutical Sciences of Shandong University collaborated in publishing a research paper entitled "Discovery of Novel Src Homology‑2 Domain-Containing Phosphatase 2 and Histone Deacetylase Dual Inhibitors with Potent Antitumor Efficacy and Enhanced Antitumor Immunity" in Journal of Medicinal Chemistry (Q1, top journal). PhD candidate Liu Meng is the first author of this paper.

Both Src homology-2 domain-containing phosphatase 2 (SHP2) and histone deacetylase (HDAC) are important oncoproteins and potential immunomodulators. In this study, the research group first observed a synergistic antiproliferation effect of an allosteric SHP2 inhibitor (SHP099) and HDAC inhibitor (SAHA) in MV4-11 cells. Inspired by this result, they developed a series of SHP2/HDAC dual inhibitors based on the pharmacophore fusion strategy. The most potent compound 8t exhibited improved antitumor activities compared with those of SHP099 and SAHA in vitro and in vivo. This 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. In summary, this study reported the first SHP2/HDAC dual inhibitor and could serve as a promising lead compound for cancer immunotherapy.

Professor Fang Hao's research group focuses on the development of new small molecular anti-cancer drugs. In previous studies, they have designed the HDAC/Proteasome dual inhibitor (J. Med. Chem. 2020, 63:4701), HDAC/Bax bifunctional ligand (J. Med. Chem. 2020, 63: 12083) as well as DNA-targeting HDAC inhibitor (J. Med. Chem. 2022, 65: 3667). The relevant research results have been authorized by a number of Chinese invention patents, one of which is under the process of PCT international patent application and cooperation with pharmaceutical companies to carry out the joint development of new drugs. The above research were supported by the National Natural Science Foundation of China.

Link:

https://pubs.acs.org/doi/10.1021/acs.jmedchem.2c00866