3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) based molecules as potent, dual inhibitors of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1): structure-based design and structure-activity relationship studies.

doi:10.1021/jm101181u

Paper

3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) based molecules as potent, dual inhibitors of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1): structure-based design and structure-activity relationship studies.

Published Jan 14, 2011 · Zhichao Zhang, Guiye Wu, Feibo Xie

Journal of medicinal chemistry

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75

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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.

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Study Snapshot

3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1) is a potent dual inhibitor of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

Paper

3-Thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (S1) based molecules as potent, dual inhibitors of B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia sequence 1 (Mcl-1): structure-based design and structure-activity relationship studies.

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Citations

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Therapeutic advancements in targeting BCL-2 family proteins by epigenetic regulators, natural, and synthetic agents in cancer.

Targeting BCL-2 family proteins with epigenetic regulators, natural, and synthetic agents has shown promise in developing cancer therapeutics.

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The study developed a selective Mcl-1 inhibitor A4 with 5-fold selectivity over Bcl-2 and a dual Mcl-1/Bcl-2 inhibitor B3 with optimized affinities, both showing promising apoptosis-inducing potencies against cancer cells.

Trends in targeting Bcl-2 anti-apoptotic proteins for cancer treatment.

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