Design, in silico evaluation, and in vitro verification of new bivalent Smac mimetics with pro-apoptotic activity

• Published in: Methods (San Diego, Calif.) Vol. 224; pp. 35 - 46
• Main Authors: Huang, Qingsheng, Peng, Yin, Peng, Yuefeng, Lin, Huijuan, Deng, Shiqi, Feng, Shengzhong, Wei, Yanjie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2024
• Subjects: Antagonist; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Caspase-3; Caspase-9; caspases; cell growth; Cell Line, Tumor; computer simulation; growth retardation; Humans; Inhibitor of Apoptosis Proteins - metabolism; Inhibitor of Apoptosis Proteins - pharmacology; Molecular Conformation; neoplasm cells; Neoplasms; prediction; Smac mimetic; X-Linked Inhibitor of Apoptosis Protein - metabolism; X-Linked Inhibitor of Apoptosis Protein - pharmacology; XIAP; XIAP; Smac mimetic; Antagonist; Caspase-3; Caspase-9; Apoptosis
• ISSN: 1046-2023; 1095-9130; 1095-9130
• DOI: 10.1016/j.ymeth.2024.02.004

•Five bivalent Smac mimetics are designed and synthesised.•Mimetics are evaluated in silico with the TwistDock workflow.•Compound 3 among the five displays the highest binding potency to BIR2 and BIR3.•Experiments with SK-OV-3 and MDA-MB-231 cancer cell lines confirm the prediction. Bivalent Smac mimetics have been shown to possess binding affinity and pro-apoptotic activity similar to or more potent than that of native Smac, a protein dimer able to neutralize the anti-apoptotic activity of an inhibitor of caspase enzymes, XIAP, which endows cancer cells with resistance to anticancer drugs. We design five new bivalent Smac mimetics, which are formed by various linkers tethering two diazabicyclic cores being the IAP binding motifs. We built in silico models of the five mimetics by the TwistDock workflow and evaluated their conformational tendency, which suggests that compound 3, whose linker is n-hexylene, possess the highest binding potency among the five. After synthesis of these compounds, their ability in tumour cell growth inhibition and apoptosis induction displayed in experiments with SK-OV-3 and MDA-MB-231 cancer cell lines confirms our prediction. Among the five mimetics, compound 3 displays promising pro-apoptotic activity and deserves further optimization.