RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) 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 with 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... More
RUVBL1 and RUVBL2 are ATPases associated with diverse cellular activities (AAAs) 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 with 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.
