Structure‐based design, synthesis, and evaluation of Bcl‐2/Mcl‐1 dual inhibitors

• Published in: Archiv der Pharmazie (Weinheim) 2020-05, Vol.353 (5), p.e2000005-n/a
• Main Authors: Zhu, Junjie, Wang, Ziqian, Guo, Zongwei, Zhang, Xiaodong, Song, Ting, Guo, Yafei, Ji, Tong, Zhang, Zhichao
• Format: Article
• Language: English
• Subjects: anticancer activities; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; Bcl‐2/Mcl‐1 dual inhibitor; Cell Line, Tumor; Cell Proliferation - drug effects; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; HEK293 Cells; Humans; Molecular Docking Simulation; Molecular Structure; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Phenalenes - chemical synthesis; Phenalenes - chemistry; Phenalenes - pharmacology; Proto-Oncogene Proteins c-bcl-2 - antagonists & inhibitors; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202000005

Based on our previously reported Bcl‐2/Mcl‐1 dual inhibitor 4‐thiomorpholinyl‐2‐cyano‐3‐amidinophenalenone (A1) that simultaneously occupies the p2 and p4 hydrophobic pockets of Bcl‐2 and Mcl‐1, we optimized molecules with different bond angles of the groups extending to the p4 pocket and bulky hydrophobic groups to explore p2. Research on structure–activity relationship resulted in a new derivative B4 that is capable of occupying both the p2 and p4 more deeply and completely than A1, with Ki values determined by fluorescence polarization assay (FPAs) improving to 0.31 μM for Bcl‐2 and 0.16 μM for Mcl‐1. Furthermore, B4 exhibited selective lethality on cancer cells over normal cells. It showed stronger apoptosis induction than (–)‐gossypol on a Bcl‐2/Mcl‐1‐dependent cancer cell line and killed an Mcl‐1‐dependent cell line which is resistant to ABT‐199 treatment. Optimization of the previously reported Bcl‐2/Mcl‐1 dual inhibitor 4‐thiomorpholinyl‐2‐cyano‐3‐amidinophenalenone (A1) resulted in a new derivative B4 that is capable of occupying both the p2 and p4 hydrophobic pockets of Bcl‐2 and Mcl‐1 more deeply and completely than A1. B4 shows selective lethality on cancer cells over normal cells and stronger apoptosis induction than (–)‐gossypol on a Bcl‐2/Mcl‐1‐dependent cancer cell line.