Potent and selective small-molecule MCL-1 inhibitors demonstrate on-target cancer cell killing activity as single...

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• MCL-1 is a critical anti-apoptotic protein promoting cancer cell survival.
• It confers resistance to existing BCL-2 family inhibitors like navitoclax.
• Targeting MCL-1 is challenging due to high-affinity protein-protein interactions.

Purpose of the Study:

• To design and characterize novel small molecules that potently inhibit MCL-1.
• To evaluate the efficacy of these inhibitors in inducing cancer cell apoptosis.
• To explore the therapeutic potential of MCL-1 inhibitors in cancer treatment.

Main Methods:

• Synthesis and screening of indole-2-carboxylic acid derivatives.
• Biochemical assays to assess binding affinity to MCL-1.
• Cell-based assays including BH3 profiling and siRNA rescue to determine MCL-1 dependency.
• Assessment of apoptosis induction and synergistic effects with navitoclax.

Main Results:

• Identified A-1210477, a potent and selective MCL-1 inhibitor.
• A-1210477 disrupts MCL-1-BIM interactions and induces apoptosis in cancer cells.
• Demonstrated single-agent activity against MCL-1-dependent multiple myeloma and NSCLC cell lines.
• Showed synergistic killing of cancer cells when combined with navitoclax.

Conclusions:

• Developed the first potent small-molecule MCL-1 inhibitors with demonstrated cellular activity.
• These inhibitors serve as valuable chemical tools for studying MCL-1 biology.
• Small-molecule MCL-1 inhibitors hold significant therapeutic promise for cancer treatment.