title: Novel Mcl-1/Bcl-2 dual inhibitors created by the structure-based hybridization of drug-divided building blocks and a fragment deconstructed from a known two-face BH3 mimetic.
abstract: We have previously reported a small-molecule two-face Bim BH3 mimetic, 2,3-dihydroxy-6-(4-isopropylphenylthio)anthracene-9,10-dione (1). Herein, we linked a polyphenol fragment, which was deconstructed from compound 1, with a drug-derived building block gained from computer-aided molecular design. 2-Phenyl-1H-benzo[d]imidazole as a new scaffold for two-face Bim mimetics was developed; based on this, a series of Mcl-1/Bcl-2 dual inhibitors were obtained. The most potent compound 6d binds to Mcl-1 and Bcl-2 with K(i) values of 127 and 607 nM, respectively, and effectively induces apoptosis in a dose-dependent, mechanism-based manner in multiple cancer cell lines.
authors: State Key Laboratory of Fine Chemicals School of Chemistry, Dalian University of Technology, Dalian, P. R. China.
authors: Zhichao
authors: Z
authors: Zhang
authors: Pengchen
authors: P
authors: Su
authors: Xiangqian
authors: X
authors: Li
authors: Ting
authors: T
authors: Song
authors: Gaobo
authors: G
authors: Chai
authors: Xiaoyan
authors: X
authors: Yu
authors: Keren
authors: K
authors: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D032701:Biomimetics / Q000379:methods*; D002470:Cell Survival / Q000187:drug effects; D017076:Computer-Aided Design; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D058990:Molecular Targeted Therapy; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000494:pharmacology*; D011487:Protein Conformation; D011518:Proto-Oncogene Proteins / Q000138:chemical synthesis* / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; C474007:Bax protein (53-86); C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2
keywords: Bcl-2; Drug-divided building blocks; Fragment-based; Mcl-1; α-Helix