CB-6644 is an Inhibitor of the RUVBL1/2 Complex
Posted On 2019-05-01
RUVBL1 and RUVBL2 are related ATPase associated with diverse cellular activities proteins. RUVBL2 is a human gene coding for a protein belonged to the diverse cellular activities family of proteins. RUVBL1 can form a hexamer with RUVBL2 protein. Both RUVBL1 and RUVBL2 can bind to nucleosomes. RUVBL1 and RUVBL2 form a complex to participate in a variety of cellular processes. These processes include chromatin remodeling and regulation of gene expression. RUVBLs have a strong link to oncogenesis, where overexpression correlates with tumor growth and poor prognosis in several cancer types. Assimon VA, et al. identified CB-6644 as a potent and selective inhibitor of the RUVBL1/2 Complex.
CB-6644 has potent antitumor activity with low toxicity.
CB-6644 acts as a noncompetitive ATPase inhibitor. Additionally, it can inhibit RUVBL1/2 ATPase activity without blocking nucleotide binding. CB-6644 also interacts with the RUVBL1/2 complex in cells and induces cancer Ramos cell death. Besides, CB-6644 binds to and stabilizes RUVBL1/2 in Ramos cells. 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. Moreover, CB-6644 offers a therapeutic approach to target cancer and a chemical probe to better understand RUVBL biology. On the other hand, CB-6644 activates the p53 and p21 pathways. CB-6644 treatment leads to a dose-dependent accumulation of both p53 and p21 with EC50 values of 0.24±0.03 and 0.15±0.07 μM, respectively. CB-6644 causes a strong p53 and p21 pathway response in cancer cells that is specifically due to chemical perturbation of RUVBL1/2.
In vivo, CB-6644 has antitumor activity in xenograft tumor models. In xenograft models of acute myeloid leukemia and multiple myeloma, CB-6644 significantly reduces tumor growth without obvious toxicity.
All in all, CB-6644 is a selective non-ATP-competitive inhibitor of the RUVBL1/2 complex and offers a novel therapeutic approach for cancer treatment.
Assimon VA, et al. ACS Chem Biol. 2019 Feb 15;14(2):236-244.