Identification of a novel BCL2-specific inhibitor that binds predominantly to the BH1 domain

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• The antiapoptotic protein BCL2 is frequently overexpressed in various cancers, promoting cell survival and chemoresistance.
• BCL2 overexpression makes it a significant therapeutic target for developing novel cancer treatments.

Purpose of the Study:

• To design, synthesize, and characterize Disarib, a novel inhibitor targeting BCL2.
• To investigate Disarib's mechanism of action and specificity.

Main Methods:

• In silico, biochemical, and biophysical assays were employed to assess Disarib's binding affinity and specificity.
• Cytotoxicity assays were performed on cancer cell lines with varying BCL2 expression levels and primary patient cells.
• Gene knockdown and ectopic expression studies were conducted to confirm target specificity.

Main Results:

• Disarib demonstrated selective cytotoxicity against BCL2-high cancer cell lines and chronic lymphocytic leukemia (CLL) patient cells.
• Target specificity was confirmed by BCL2 knockdown conferring resistance and ectopic expression restoring sensitivity.
• Biophysical studies revealed Disarib's strong affinity for BCL2, with predominant interaction involving the BH1 domain, distinguishing it from BH3-targeting inhibitors.

Conclusions:

• Disarib is a novel BCL2 inhibitor with selective cytotoxicity in relevant cancer models.
• Disarib exhibits a unique mechanism of action, primarily engaging the BH1 domain of BCL2.
• This discovery presents a promising new therapeutic avenue for BCL2-driven cancers.