Abstract
5-Butyl-1,4-diphenyl pyrazole and 2-amino-5-chloro pyrimidine acylsulfonamides were developed as potent dual antagonists of Bcl-2 and Bcl-xL. Compounds were optimized for binding to the I88, L92, I95, and F99 pockets normally occupied by pro-apoptotic protein Bim. An X-ray crystal structure confirmed the proposed binding mode. Observation of cytochrome c release from isolated mitochondria in MV-411 cells provides further evidence of target inhibition. Compounds demonstrated submicromolar antiproliferative activity in Bcl-2/Bcl-xL dependent cell lines.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis Regulatory Proteins / chemistry
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Binding Sites
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Cell Line, Tumor
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Crystallography, X-Ray
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Cytochromes c / metabolism
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Humans
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Membrane Proteins / chemistry
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Membrane Proteins / metabolism
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Mitochondria / drug effects
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Mitochondria / metabolism
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Models, Molecular
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Protein Binding
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Proto-Oncogene Proteins / chemistry
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Proto-Oncogene Proteins / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / pharmacology
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology
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bcl-2-Associated X Protein / antagonists & inhibitors*
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bcl-2-Associated X Protein / chemistry
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bcl-2-Associated X Protein / metabolism
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bcl-X Protein / antagonists & inhibitors*
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bcl-X Protein / chemistry
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bcl-X Protein / metabolism
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Membrane Proteins
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Proto-Oncogene Proteins
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Pyrazoles
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Pyrimidines
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Sulfonamides
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bcl-2-Associated X Protein
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bcl-X Protein
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Cytochromes c