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Structure-Guided Discovery of a Selective Mcl-1 Inhibitor with Cellular Activity

Zoltan Szlávik1, Levente Ondi1, Márton Csékei1

  • 1Servier Research Institute of Medicinal Chemistry , Záhony u. 7. , H-1031 Budapest , Hungary.

Journal of Medicinal Chemistry
|July 25, 2019
PubMed

Insights

Researchers discovered selective small molecule inhibitors targeting Myeloid cell leukemia 1 (Mcl-1), a protein linked to cancer progression and treatment resistance. These novel compounds show potent cellular activity, offering a promising new avenue for cancer therapy development.

Area of Science:

  • Oncology
  • Medicinal Chemistry
  • Molecular Biology

Background:

  • Myeloid cell leukemia 1 (Mcl-1) is an antiapoptotic protein upregulated in human cancers.
  • Mcl-1 overexpression correlates with high tumor grade, poor survival, and chemotherapy resistance.
  • Mcl-1 is an attractive therapeutic target for cancer treatment.

Purpose of the Study:

  • To discover and optimize selective small molecule inhibitors of Mcl-1.
  • To develop novel compounds with potent anti-cancer activity.

Main Methods:

  • Fragment screening identified initial thienopyrimidine amino acid hits.
  • Structure-based drug design using NMR and X-ray crystallography for optimization.
  • Chemical modifications to enhance selectivity and cellular efficacy.

Main Results:

  • Optimized compounds exhibit nanomolar binding affinity for Mcl-1.
  • Achieved high selectivity through hindered rotation along a biaryl axis.
  • Demonstrated mechanism-based cellular efficacy, including caspase induction and growth inhibition.
  • Identified lead compounds S63845 and S64315.

Conclusions:

  • Successful optimization of thienopyrimidine hits into potent and selective Mcl-1 inhibitors.
  • The developed compounds show significant anti-cancer potential.
  • These findings represent a significant advancement in Mcl-1 targeted cancer therapy.

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