Structure-guided design of a series of MCL-1 inhibitors with high affinity and selectivity

J Med Chem. 2015 Mar 12;58(5):2180-94. doi: 10.1021/jm501258m. Epub 2015 Feb 26.


Myeloid cell leukemia 1 (MCL-1) is a BCL-2 family protein that has been implicated in the progression and survival of multiple tumor types. Herein we report a series of MCL-1 inhibitors that emanated from a high throughput screening (HTS) hit and progressed via iterative cycles of structure-guided design. Advanced compounds from this series exhibited subnanomolar affinity for MCL-1 and excellent selectivity over other BCL-2 family proteins as well as multiple kinases and GPCRs. In a MCL-1 dependent human tumor cell line, administration of compound 30b rapidly induced caspase activation with associated loss in cell viability. The small molecules described herein thus comprise effective tools for studying MCL-1 biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Survival / drug effects
  • Crystallography, X-Ray
  • Databases, Factual
  • Drug Design*
  • High-Throughput Screening Assays
  • Humans
  • Molecular Docking Simulation
  • Molecular Structure
  • Multiple Myeloma / drug therapy*
  • Multiple Myeloma / metabolism
  • Multiple Myeloma / pathology
  • Myeloid Cell Leukemia Sequence 1 Protein / chemistry*
  • Myeloid Cell Leukemia Sequence 1 Protein / metabolism
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Protein Binding
  • Structure-Activity Relationship
  • Tumor Cells, Cultured


  • Antineoplastic Agents
  • MCL1 protein, human
  • Myeloid Cell Leukemia Sequence 1 Protein