Abstract
Bcl-2 and Bcl-xL antiapoptotic proteins are attractive cancer therapeutic targets. We have previously reported the design of 4,5-diphenyl-1H-pyrrole-3-carboxylic acids as a class of potent Bcl-2/Bcl-xL inhibitors. In the present study, we report our structure-based optimization for this class of compounds based upon the crystal structure of Bcl-xL complexed with a potent lead compound. Our efforts accumulated into the design of compound 30 (BM-957), which binds to Bcl-2 and Bcl-xL with K(i) < 1 nM and has low nanomolar IC(50) values in cell growth inhibition in cancer cell lines. Significantly, compound 30 achieves rapid, complete, and durable tumor regression in the H146 small-cell lung cancer xenograft model at a well-tolerated dose schedule.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / chemistry
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Antineoplastic Agents / pharmacology
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Carcinoma, Non-Small-Cell Lung / drug therapy
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Carcinoma, Non-Small-Cell Lung / pathology
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Screening Assays, Antitumor
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Humans
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Lung Neoplasms / drug therapy
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Lung Neoplasms / pathology
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Mice
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Mice, SCID
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Neoplasm Transplantation
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Protein Conformation
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Stereoisomerism
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
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Tumor Burden / drug effects
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bcl-X Protein / antagonists & inhibitors
Substances
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Antineoplastic Agents
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BM-957
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Proto-Oncogene Proteins c-bcl-2
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Pyrroles
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Sulfonamides
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bcl-X Protein