Sonrotoclax overcomes BCL2 G101V mutation-induced venetoclax resistance in preclinical models of hematologic malignancy
Venetoclax, a first-generation inhibitor targeting the anti-apoptotic protein BCL2, disrupts its interaction with pro-apoptotic proteins to promote cell death in malignant cells. It is a cornerstone treatment for relapsed chronic lymphocytic leukemia and is being evaluated in numerous clinical trials for other cancers. While venetoclax can induce durable remissions, relapse is common, often due to acquired resistance. A frequently observed resistance mechanism is the G101V mutation in BCL2, which interferes with venetoclax binding and diminishes its efficacy.
To address this challenge, we investigated sonrotoclax, a potent and selective next-generation BCL2 inhibitor. Sonrotoclax exhibited stronger cytotoxic activity across various hematologic cancer cell lines and more robust tumor growth inhibition in preclinical models compared to venetoclax. Importantly, sonrotoclax retained activity against venetoclax-resistant BCL2 mutants, including G101V. Structural analysis revealed that sonrotoclax binds to the P2 pocket of both wild-type and G101V BCL2 via a novel binding mode, offering a mechanistic explanation for its enhanced potency.
In summary, sonrotoclax represents a promising second-generation BCL2 inhibitor capable of overcoming resistance associated with BCL2 mutations. It is currently being evaluated in multiple clinical trials for hematologic malignancies.