Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics

Ziqian Wang; Ting Song; Yingang Feng; Zongwei Guo; Yudan Fan; Wenjie Xu; Lu Liu; Anhui Wang; Zhichao Zhang

doi:10.1021/acs.jmedchem.5b01913

Bcl-2/MDM2 Dual Inhibitors Based on Universal Pyramid-Like α-Helical Mimetics

J Med Chem. 2016 Apr 14;59(7):3152-62. doi: 10.1021/acs.jmedchem.5b01913. Epub 2016 Mar 22.

Authors

Ziqian Wang¹, Ting Song², Yingang Feng³, Zongwei Guo², Yudan Fan², Wenjie Xu¹, Lu Liu¹, Anhui Wang¹, Zhichao Zhang¹

Affiliations

¹ 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.
² School of Life Science and Technology, Dalian University of Technology , Dalian 116024, People's Republic of China.
³ Shandong Key Laboratory of Synthetic Biology, Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese Academy of Sciences , Qingdao 266101, People's Republic of China.

PMID: 26982372
DOI: 10.1021/acs.jmedchem.5b01913

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects*
Binding Sites
Blotting, Western
Cell Cycle / drug effects
Cell Proliferation / drug effects
Humans
Immunoenzyme Techniques
Immunoprecipitation
Magnetic Resonance Spectroscopy
Models, Molecular
Protein Binding
Protein Conformation / drug effects*
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-bcl-2 / genetics
Proto-Oncogene Proteins c-bcl-2 / metabolism
Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
Proto-Oncogene Proteins c-mdm2 / genetics
Proto-Oncogene Proteins c-mdm2 / metabolism
RNA, Messenger / genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / antagonists & inhibitors*
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Antineoplastic Agents
Proto-Oncogene Proteins c-bcl-2
RNA, Messenger
Tumor Suppressor Protein p53
Proto-Oncogene Proteins c-mdm2