Discovery of selective Mcl-1 inhibitors via structure-based design and structure-activity relationship analysis

Nianzhe He; Peng Liu; Ziqian Wang; Zongwei Guo; Xinxin Yan; Hongbo Chen; Zhichao Zhang

doi:10.1016/j.bbrc.2019.03.102

Discovery of selective Mcl-1 inhibitors via structure-based design and structure-activity relationship analysis

Biochem Biophys Res Commun. 2019 May 14;512(4):921-926. doi: 10.1016/j.bbrc.2019.03.102. Epub 2019 Mar 28.

Authors

Nianzhe He¹, Peng Liu², Ziqian Wang³, Zongwei Guo², Xinxin Yan¹, Hongbo Chen¹, Zhichao Zhang¹

Affiliations

¹ State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
² School of Life Science and Technology, Dalian University of Technology, Dalian, China.
³ Zhang Dayu School of Chemistry, Dalian University of Technology, Dalian, China. Electronic address: wangziqian@dlut.edu.cn.

PMID: 30928099
DOI: 10.1016/j.bbrc.2019.03.102

Abstract

Based on Nap-1, a Mcl-1/Bcl-2 dual inhibitor reported by our group, we carried out a structure-guided molecular design and structure-activity relationship (SAR) analysis to study structural features contributing to Mcl-1 binding selectivity and affinity. A series of derivatives of Nap-1 with various pharmacophores were synthesized and among them a dual Mcl-1/Bcl-2 inhibitor A4 with enhanced affinities (IC₅₀ = 0.15 μM for Mcl-1, 0.43 μM for Bcl-2) and a selective Mcl-1 inhibitor B9 with a 20-fold selectivity over Bcl-2 (IC₅₀ = 0.51 μM vs 9.46 μM) were obtained by enzyme linked immunosorbent assay (ELISA). The SAR data and binding modes of A4 and B9 investigated by 2D-NMR derived docking study illustrated that p2 pockets exhibiting different geometry and binding features between Mcl-1 and Bcl-2 contribute to specific binding properties of Mcl-1. In addition, apoptosis-inducing potencies of A4 and B9 were consistent with their binding selectivity determined in vitro.

Keywords: Apoptosis; Cancer; Mcl-1; Protein–protein interaction.

Publication types

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

MeSH terms

Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology*
Dose-Response Relationship, Drug
Enzyme-Linked Immunosorbent Assay
HEK293 Cells
HeLa Cells
Humans
K562 Cells
Magnetic Resonance Spectroscopy
Models, Molecular
Molecular Docking Simulation
Molecular Structure
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
Myeloid Cell Leukemia Sequence 1 Protein / chemistry
Myeloid Cell Leukemia Sequence 1 Protein / metabolism
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
Proto-Oncogene Proteins c-bcl-2 / chemistry
Proto-Oncogene Proteins c-bcl-2 / metabolism
Structure-Activity Relationship

Substances

Antineoplastic Agents
BCL2 protein, human
MCL1 protein, human
Myeloid Cell Leukemia Sequence 1 Protein
Proto-Oncogene Proteins c-bcl-2