CB-6644 is a selective inhibitor of the RUVBL1/2 complex with anti-cancer activity.

RUVBL1 and RUVBL2 are ATPases Associated with diverse cellular Activities (AAA) that form a complex involved in a variety of cellular processes including chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression is correlated to tumor growth and poor prognosis in several cancer types. CB-6644, an allosteric small molecule inhibitor of the ATPase activity of the RUVBL1/2 complex, interacts specifically with RUVBL1/2 in cancer cells leading to cell death. Importantly, drug-acquired resistant cell clones have amino acid mutations in either RUVBL1 or RUVBL2, suggesting that cell killing is an on-target consequence of RUVBL1/2 engagement. In xenograft models of acute myeloid leukemia and multiple myeloma, CB-6644 significantly reduced tumor growth without obvious toxicity. This work demonstrates the therapeutic potential of targeting RUVBLs in the treatment of cancer and establishes a chemical entity for probing the many facets of RUVBL biology.