Discovery of potent Mcl-1/Bcl-xL dual inhibitors by using a hybridization strategy based on structural analysis of target proteins

J Med Chem. 2013 Dec 12;56(23):9635-45. doi: 10.1021/jm401170c. Epub 2013 Dec 2.


Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A cocrystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein-ligand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. On the basis of the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC50 = 0.088 μM; and Bcl-xL, IC50 = 0.0037 μM).

MeSH terms

  • Aniline Compounds / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / chemistry
  • Biphenyl Compounds / pharmacology
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Models, Molecular
  • Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology
  • bcl-X Protein / antagonists & inhibitors*


  • Aniline Compounds
  • Apoptosis Regulatory Proteins
  • Biphenyl Compounds
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein
  • Pyrazoles
  • Pyridines
  • Sulfonamides
  • bcl-X Protein
  • navitoclax

Associated data

  • PDB/3WIX
  • PDB/3WIY
  • PDB/3WIZ