Abstract
Bcl-2 and Bcl-xL are key apoptosis regulators and attractive cancer therapeutic targets. We have designed and optimized a class of small-molecule inhibitors of Bcl-2 and Bcl-xL containing a 4,5-diphenyl-1H-pyrrole-3-carboxylic acid core structure. A 1.4 Å resolution crystal structure of a lead compound, 12, complexed with Bcl-xL has provided a basis for our optimization. The most potent compounds, 14 and 15, bind to Bcl-2 and Bcl-xL with subnanomolar K(i) values and are potent antagonists of Bcl-2 and Bcl-xL in functional assays. Compounds 14 and 15 inhibit cell growth with low nanomolar IC(50) values in multiple small-cell lung cancer cell lines and induce robust apoptosis in cancer cells at concentrations as low as 10 nM. Compound 14 also achieves strong antitumor activity in an animal model of human cancer.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Animals
-
Antineoplastic Agents / chemical synthesis
-
Antineoplastic Agents / chemistry*
-
Antineoplastic Agents / pharmacology*
-
Apoptosis Regulatory Proteins / metabolism
-
Cell Death / drug effects
-
Cell Line, Tumor
-
Cell Proliferation / drug effects
-
Crystallography, X-Ray
-
Drug Design
-
Drug Screening Assays, Antitumor
-
Fluorescence Polarization
-
Humans
-
Inhibitory Concentration 50
-
Mice
-
Mice, SCID
-
Models, Molecular
-
Molecular Structure
-
Neoplasms / metabolism
-
Piperazines / chemical synthesis
-
Piperazines / chemistry
-
Piperazines / pharmacology
-
Protein Binding
-
Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
-
Pyrazoles / chemical synthesis
-
Pyrazoles / chemistry*
-
Pyrazoles / pharmacology*
-
Stereoisomerism
-
Structure-Activity Relationship
-
Sulfonamides / chemical synthesis
-
Sulfonamides / chemistry*
-
Sulfonamides / pharmacology*
-
bcl-X Protein / antagonists & inhibitors*
Substances
-
5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)-butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-isopropyl-2-methyl-1H-pyrrole-3-carboxylic acid
-
5-(4-chlorophenyl)-4-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)butan-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-1-ethyl-2-methyl-1H-pyrrole-3-carboxylic acid
-
Antineoplastic Agents
-
Apoptosis Regulatory Proteins
-
BCL2L1 protein, human
-
Piperazines
-
Proto-Oncogene Proteins c-bcl-2
-
Pyrazoles
-
Sulfonamides
-
bcl-X Protein