Discovery of an Oral, Beyond-Rule-of-Five Mcl-1 Protein-Protein Interaction Modulator with the Potential of Treating...

Area of Science:

• Oncology
• Molecular Biology
• Medicinal Chemistry

Background:

• Apoptosis evasion is a hallmark of cancer, enabling tumor development and growth.
• Myeloid cell leukemia 1 (Mcl-1) is a pro-survival protein overexpressed in many cancers, correlating with poor prognosis and chemoresistance.
• Targeting Mcl-1 is a promising strategy for overcoming treatment resistance in relapsed or refractory malignancies.

Purpose of the Study:

• To design, synthesize, and optimize a novel small-molecule inhibitor of Mcl-1.
• To evaluate the preclinical efficacy and safety profile of the developed Mcl-1 inhibitor.
• To explore structure-activity relationships for improved potency and reduced cardiotoxicity.

Main Methods:

• Structure-based drug design and chemical synthesis of Mcl-1 inhibitors.
• In vitro assays to assess inhibitory potency and selectivity.
• Physicochemical property evaluation, including assessment of "non-Lipinski" characteristics.
• In vivo studies in mouse xenograft models to determine oral bioavailability and pharmacodynamic effects.

Main Results:

• A potent and selective small-molecule inhibitor of Mcl-1 was successfully designed and synthesized.
• The compound demonstrated favorable physicochemical properties and good oral bioavailability despite being beyond the Rule-of-Five.
• Pharmacodynamic studies confirmed potent Mcl-1 inhibition in a preclinical mouse xenograft model.
• Exploratory design minimized the risk of functional cardiotoxicity.

Conclusions:

• The developed Mcl-1 inhibitor represents a promising therapeutic candidate for cancers overexpressing Mcl-1.
• The compound's favorable in vivo properties support its further development for treating refractory malignancies.
• This study highlights the potential of targeting Mcl-1 with small molecules, even those with non-traditional physicochemical properties.