CB-6644 Is a Selective Inhibitor of the RUVBL1/2 Complex with Anticancer Activity

  • ACS Chem Biol. 2019 Feb 15;14(2):236-244. doi: 10.1021/acschembio.8b00904.
Victoria A Assimon  1 ,  Yangzhong Tang  1 ,  Jesse D Vargas  1 ,  Grace J Lee  1 ,  Zhi Yong Wu  1 ,  Kenny Lou  1 ,  Bing Yao  1 ,  Mary-Kamala Menon  1 ,  Ariel Pios  1 ,  Kristy C Perez  1 ,  Antonett Madriaga  1 ,  Peter K Buchowiecki  1 ,  Mark Rolfe  1 ,  Laura Shawver  1 ,  Xianyun Jiao  1 ,  Ronan Le Moigne  1 ,  Han-Jie Zhou  1 ,  Daniel J Anderson  1
Affiliations
  • 1. Cleave Biosciences, Inc. , Burlingame , California 94010 , United States.
PMID: 30640450 DOI: 10.1021/acschembio.8b00904
Abstract

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.

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