Design of Bcl-2 and Bcl-xL inhibitors with subnanomolar binding affinities based upon a new scaffold

J Med Chem. 2012 May 24;55(10):4664-82. doi: 10.1021/jm300178u. Epub 2012 May 10.


Employing a structure-based strategy, we have designed a new class of potent small-molecule inhibitors of the anti-apoptotic proteins Bcl-2 and Bcl-xL. An initial lead compound with a new scaffold was designed based upon the crystal structure of Bcl-xL and U.S. Food and Drug Administration (FDA) approved drugs and was found to have an affinity of 100 μM for both Bcl-2 and Bcl-xL. Linking this weak lead to another weak-affinity fragment derived from Abbott's ABT-737 led to an improvement of the binding affinity by a factor of >10 000. Further optimization ultimately yielded compounds with subnanomolar binding affinities for both Bcl-2 and Bcl-xL and potent cellular activity. The best compound (21) binds to Bcl-xL and Bcl-2 with K(i) < 1 nM, inhibits cell growth in the H146 and H1417 small-cell lung cancer cell lines with IC(50) values of 60-90 nM, and induces robust cell death in the H146 cancer cell line at 30-100 nM.

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

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Cell Death / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Drug Screening Assays, Antitumor
  • Fluorescence Polarization
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Binding
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • bcl-X Protein / antagonists & inhibitors


  • 4-(4-chlorophenyl)-3-(3-(4-(4-(4-((4-(dimethylamino)-1-(phenylthio)but-2-yl)amino)-3-nitrophenylsulfonamido)phenyl)piperazin-1-yl)phenyl)-5-ethyl-1-methyl-1H-pyrrole-2-carboxylic acid
  • Antineoplastic Agents
  • Piperazines
  • Proto-Oncogene Proteins c-bcl-2
  • Sulfonamides
  • bcl-X Protein

Associated data

  • PDB/3SPF