CB-6644

• CAS: 2316817-88-4
• Catalog Number: ACM2316817884
• Category: Inhibitors
• Molecular Weight: 573.06
• Molecular Formula: C29H34ClFN4O5
• Description: CB-6644 is a novel allosteric selective inhibitor of the ruvbl1/2 complex with anti-cancer activity. CB-6644 blocks the ATPase activity of RUVBL1/2 with an IC50 of 15 nM. CB-6644 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.
• Synonyms: CB-6644; CB 6644; CB6644
• IUPAC Name: 5-Chloro-2-ethoxy-4-fluoro-N-(4-((3-(methoxymethyl)-1-oxo-6,7-dihydro-1H,5H-benzo[c]pyrazolo[1,2-a][1,2]diazepin-2-yl)amino)-2,2-dimethyl-4-oxobutyl)benzamide
• Canonical SMILES: O=C(NCC(C)(C)CC(NC(C1=O)=C(COC)N2N1C3=CC=CC=C3CCC2)=O)C4=CC(Cl)=C(F)C=C4OCC
• InChI: InChI=1S/C29H34ClFN4O5/c1-5-40-24-14-21(31)20(30)13-19(24)27(37)32-17-29(2,3)15-25(36)33-26-23(16-39-4)34-12-8-10-18-9-6-7-11-22(18)35(34)28(26)38/h6-7,9,11,13-14H,5,8,10,12,15-17H2,1-4H3,(H,32,37)(H,33,36)
• InChI Key: VYCOZEBCSAQCES-UHFFFAOYSA-N
• Solubility: Soluble in DMSO
• Appearance: Solid powder
• Shelf Life: >3 years if stored properly
• Storage: Dry, dark and at 0-4 °C for short term (days to weeks) or -20 °C for long term (months to years).
• Biological Target: RUVBL1/2 with an IC50 of 15 nM.
• Drug Formulation: This drug may be formulated in DMSO
• Elemental Analysis: C, 60.78; H, 5.98; Cl, 6.19; F, 3.32; N, 9.78; O, 13.96
• Exact Mass: 572.2202
• HS Tariff Code: 2934.99.9001
• In Vitro Activity: CB6644 blocked the ATPase activity of RUVBL1/2 with a half-maximal inhibitory concentration (IC50) of 15 nM. CB-6644 was tested against a small panel of related AAA ATPases in an ATPase assay and observed no appreciable activity (IC50 > 100 μM). CB-6644-induced cell killing may be a consequence of cell-cycle disruption. CB-6644 causes a strong p53 and p21 pathway response in cancer cells that is specifically due to chemical perturbation of RUVBL1/2. Reference: ACS Chem. Biol. 2019, 14, 2, 236-244
• In Vivo Activity: CB-6644 was administered by oral gavage once (QD) or twice (BID) daily, and tumor growth inhibition (TGI) was calculated on the last day of treatment (Figure 7b,c). This dosing schedule was well-tolerated in tumor-bearing mice, with less than 5% body weight loss throughout the studies (Figure S6). Both regimens showed antitumor activity in Ramos and RPMI8226, with the BID dosing regimen showing greater efficacy than the QD schedule (TGI of 68 and 81% in Ramos and RPMI8226, respectively). These data provide the strongest validation to date of RUVBL1/2 as a promising therapeutic cancer target. Figure 6. CB-6644 activates the p53 and p21 pathways. (a, b) A-375 cells were treated with 1 μM CB-6644 for 24 h and profiled by DriverMap for transcriptome changes. GO terms are listed for genes that were at least 3-fold (a) upregulated or (b) downregulated. (c-e) p21 and p53 were evaluated by IF in HCT116 (c) WT or (d) resistant cell lines treated with a dose titration of CB-6644. Each data point represents the mean of eight technical replicates (±SEM). (e) Example images of HCT116 WT or resistant cell lines treated with 1.25 μM CB-6644 and labeled with anti-p21 and anti-p53 antibodies. Reference: ACS Chem. Biol. 2019, 14, 2, 236-244
• Shipping: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
• Stock Solution Storage: 0-4 °C for short term (days to weeks), or -20 °C for long term (months).