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Discovery of a Copper-Based Mcl-1 Inhibitor as an Effective Antitumor Agent.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Sep 10; Vol. 63 (17), pp. 9154-9167. Date of Electronic Publication: 2020 Aug 28. - Publication Year :
- 2020
-
Abstract
- Myeloid cell leukemia 1 (Mcl-1), which belongs to the Bcl-2 family of prosurvival proteins, is a key regulator of cancer cell survival. To date, few drug-like Mcl-1 inhibitors have been reported. Herein, we report the preparation of 10 copper complexes with 9-substituted β-carboline ligands that act as metal-based Mcl-1 inhibitors. Complex 14 was identified as a potent and selective Mcl-1 inhibitor with strong in vitro antitumor activity. Mechanistic studies demonstrated that complex 14 disrupted Mcl-1-Bax/Bak heterodimerization and induced Bax/Bak-dependent apoptosis. In addition, complex 14 significantly ( P < 0.001) inhibited tumor growth in vivo , induced tumor necrosis, and extended survival time in an NCI-H460 xenograft model. Furthermore, complex 14 showed no apparent toxicity in mice. Together, these findings indicate that complex 14 is a copper-based Mcl-1 inhibitor with high efficacy and low toxicity that could be developed for the treatment of Mcl-1-related cancers.
- Subjects :
- Animals
Antineoplastic Agents metabolism
Antineoplastic Agents pharmacology
Antineoplastic Agents therapeutic use
Apoptosis drug effects
Binding Sites
Cell Line, Tumor
Coordination Complexes metabolism
Coordination Complexes pharmacology
Coordination Complexes therapeutic use
Crystallography, X-Ray
Dimerization
Humans
Kaplan-Meier Estimate
Mice
Molecular Conformation
Molecular Docking Simulation
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Neoplasms drug therapy
Neoplasms mortality
Neoplasms pathology
Protein Binding
Structure-Activity Relationship
Transplantation, Heterologous
Antineoplastic Agents chemistry
Coordination Complexes chemistry
Copper chemistry
Drug Design
Myeloid Cell Leukemia Sequence 1 Protein antagonists & inhibitors
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32794745
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b02047