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

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.