Apoptosis is an essential process for eliminating aging or abnormal cells in the living system. Dysregulation of apoptosis is critical for various malignant tumor diseases and drug resistance in anti-tumor therapies. Bcl-2 family proteins are key regulators of the mitochondrial apoptotic pathway. Studies have shown that overexpression of the anti-apoptotic proteins is resistant to chemotherapies in a variety of tumor cells. Therefore, blocking the protein-protein interactions formed by the anti-apoptotic proteins by small-molecule inhibitors can release the apoptotic signal, recover the inherent apoptosis process and achieve the goal of eliminating tumors.
Professor Renxiao Wang’s group from the Department of Medicinal Chemistry of our school targets the protein-protein interaction formed by the apoptosis regulators Bcl-2 family proteins, and applies drug design technology to actively develop small-molecule compounds that can regulate the functions of these molecular targets. Key progress has been made recently. The relevant results are titled Structure-Based Optimization of 3‑Phenyl‑N‑(2-(3-phenylureido)ethyl)thiophene-2-sulfonamide Derivatives as Selective Mcl‑1 Inhibitors, published online in Journal of Medicinal Chemistry, an authoritative journal in the field of medicinal chemistry published by the American Chemical Society (link: https://doi.org/10.1021/acs.jmedchem.1c00690).
The research group discovered a class of biphenyltetrazole-based lead compounds through the virtual screening of the target protein based on multiple conformations, and obtained the biphenylthiophene-based lead compounds via “core-hopping”. Further applying the optimization strategy of replacing the high-energy water molecules in the protein binding pocket helped to increase the affinity of the compounds with the target by about 30 times, and significantly improved their synthesis and bioavailability. 15N-HSQC NMR spectroscopy and immunoprecipitation experiments confirmed the specific interactions formed between some key compounds and the Mcl-1 protein. The results of pharmacodynamic experiments on the RS4;11 xenograft mouse model showed that after three weeks of intraperitoneal injection at a dose of 25 mg/kg, the tumor volume of the administered mice was reduced by more than 70% compared with the negative control group, and the continuous dosing had no effect on the body weight and survival rate of mice.
In this work, the research group made full use of its expertise in targeted molecular design and successfully obtained a class of active compounds with a novel scaffold, which showed good selectivity for Mcl-1 protein, and are expected to be promoted to candidate drugs. It can be used in combination with existing Bcl-2 protein inhibitors to provide new opportunities for the treatment of lymphoma, leukemia and other cancers. Associate professor Yan Li from the Department of Medicinal Chemistry and 2019 PhD candidate Gong Qineng are the co-first authors of this paper. This research work was supported by the National Key Research and Development Program of the Ministry of Science and Technology, the National Natural Science Foundation of China and other projects. During the research process, it was also supported by Professor Zhichao Zhang of Dalian University of Technology and Researcher Ran Hong of the Shanghai Institute of Organic Chemistry of the Chinese Academy of Sciences.