title: Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics.
abstract: No α-helical mimetic that exhibits Bcl-2/MDM2 dual inhibition has been rationally designed due to the different helicities of the α-helixes at their binding interfaces. Herein, we extracted a one-turn α-helix-mimicking ortho-triarene unit from o-phenylene foldamers. Linking benzamide substrates with a rotatable C-N bond, we constructed a novel semirigid pyramid-like scaffold that could support its two-turn α-helix mimicry without aromatic stacking interactions and could adopt the different dihedral angles of the key residues of p53 and BH3-only peptides. On the basis of this universal scaffold, a series of substituent groups were installed to capture the key residues of both p53TAD and BimBH3 and balance the differences of the bulks between them. Identified by FP, ITC, and NMR spectroscopy, a compound 6e (zq-1) that directly binds to Mcl-1, Bcl-2, and MDM2 with balanced submicromolar affinities was obtained. Cell-based experiments demonstrated its antitumor ability through Bcl-2/MDM2 dual inhibition simultaneously.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology , No. 158-89, Zhongshan Road, Dalian 116012, People's Republic of China.
authors.forename: Ziqian
authors.initials: Z
authors.lastname: Wang
authors.affiliation: School of Life Science and Technology, Dalian University of Technology , Dalian 116024, People's Republic of China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.affiliation: Shandong Key Laboratory of Synthetic Biology, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences , Qingdao 266101, People's Republic of China.
authors.forename: Yingang
authors.initials: Y
authors.lastname: Feng
authors.affiliation: School of Life Science and Technology, Dalian University of Technology , Dalian 116024, People's Republic of China.
authors.forename: Zongwei
authors.initials: Z
authors.lastname: Guo
authors.affiliation: School of Life Science and Technology, Dalian University of Technology , Dalian 116024, People's Republic of China.
authors.forename: Yudan
authors.initials: Y
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology , No. 158-89, Zhongshan Road, Dalian 116012, People's Republic of China.
authors.forename: Wenjie
authors.initials: W
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology , No. 158-89, Zhongshan Road, Dalian 116012, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology , No. 158-89, Zhongshan Road, Dalian 116012, People's Republic of China.
authors.forename: Anhui
authors.initials: A
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology , No. 158-89, Zhongshan Road, Dalian 116012, People's Republic of China.
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation / Q000187:drug effects*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2