Cleave Biosciences, Inc. , Burlingame , California 94010 , United States.
ACS Chem Biol. 2019 Feb 15;14(2):236-244. doi: 10.1021/acschembio.8b00904. Epub 2019 Jan 25.
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.
RUVBL1 和 RUVBL2 是与多种细胞活动（AAA）相关的 ATP 酶，它们形成一个涉及多种细胞过程的复合物，包括染色质重塑和基因表达调控。RUVBLs 与肿瘤发生有很强的联系，在几种癌症类型中，过度表达与肿瘤生长和预后不良相关。CB-6644 是 RUVBL1/2 复合物的 ATP 酶活性的别构小分子抑制剂，它在癌细胞中与 RUVBL1/2 特异性相互作用，导致细胞死亡。重要的是，获得药物抗性的细胞克隆在 RUVBL1 或 RUVBL2 中都有氨基酸突变，这表明细胞杀伤是 RUVBL1/2 结合的一个直接后果。在急性髓细胞白血病和多发性骨髓瘤的异种移植模型中，CB-6644 显著减少了肿瘤生长，而没有明显的毒性。这项工作证明了靶向 RUVBLs 治疗癌症的治疗潜力，并为研究 RUVBL 生物学的多个方面建立了一种化学实体。
