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

被引：71

作者：

Assimon, Victoria A. ^{[1
]}

Tang, Yangzhong ^{[1
]}

Vargas, Jesse D. ^{[1
]}

Lee, Grace J. ^{[1
]}

Wu, Zhi Yong ^{[1
]}

Lou, Kenny ^{[1
]}

Yao, Bing ^{[1
]}

Menon, Mary-Kamala ^{[1
]}

Pios, Ariel ^{[1
]}

Perez, Kristy C. ^{[1
]}

Madriaga, Antonett ^{[1
]}

Buchowiecki, Peter K. ^{[1
]}

Rolfe, Mark ^{[1
]}

Shawver, Laura ^{[1
]}

Jiao, Xianyun ^{[1
]}

Le Moigne, Ronan ^{[1
]}

Zhou, Han-Jie ^{[1
]}

Anderson, Daniel J. ^{[1
]}

机构：

[1] Cleave Biosci Inc, Burlingame, CA 94010 USA

来源：

ACS CHEMICAL BIOLOGY | 2019年 / 14卷 / 02期

关键词：

CHROMATIN REMODELING COMPLEX; INCREASED PONTIN EXPRESSION; HEPATOCELLULAR-CARCINOMA; ATPASE ACTIVITY; TERMINAL TAIL; REPTIN; INO80; CANCER; PONTIN/REPTIN; GROWTH;

D O I：

10.1021/acschembio.8b00904

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：236 / 244

页数：9

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