Abstract
We recently described the discovery of a dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1). Here we report a structure-guided design in combination with structure-activity relationship studies to exploit the difference in the p2 binding pocket of Bcl-2 and Mcl-1, from which a novel dual inhibitor 3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (6h) was obtained, which showed significant enhanced IC(50) value against Mcl-1 (5 nM), greater Mcl-1/Bak disruption potential, and accordingly a 10-fold increased cytotoxicity over 3.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acenaphthenes
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacology
-
Binding, Competitive
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
Humans
-
Inhibitory Concentration 50
-
Lymphoma, B-Cell / drug therapy*
-
Lymphoma, B-Cell / metabolism
-
Magnetic Resonance Spectroscopy
-
Mass Spectrometry
-
Morpholines / chemical synthesis
-
Morpholines / chemistry*
-
Morpholines / pharmacology
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
-
Proto-Oncogene Proteins c-bcl-2 / metabolism
-
Pyrroles / chemical synthesis
-
Pyrroles / chemistry*
-
Pyrroles / pharmacology
-
Structure-Activity Relationship
Substances
-
8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile
-
Acenaphthenes
-
Antineoplastic Agents
-
MCL1 protein, human
-
Morpholines
-
Myeloid Cell Leukemia Sequence 1 Protein
-
Proto-Oncogene Proteins c-bcl-2
-
Pyrroles