CPI-203 is a potent, selective and cell permeable inhibitor of the bromodomain and extra terminal (BET) family protein BRD4 with an IC50 of ~37 nM. CPI-203 inhibits BRD4 in vitro and in cells, but it does not affect BRD4 kinase activity in vitro. CPI203 exerts a cytostatic effect in all the 9 MCL cell lines analyzed with GI50 ranging from 0.06 to 0.71 μM), with low cytotoxicity in normal PBMCs from healthy donors. CPI-203 arrests the growth of leukemic T cells in vitro (EC50 = 91 nM) and rapidly suppresses leukemia burden in mice. In contrast, in vivo, specific Ser2 phosphorylation by either endogenous BRD4 or exogenous BRD4 FEE-AAA was markedly decreased by treatment with the inhibitor.
|Source||Genes Dev (2015). Figure 6. CPI-203|
|Cell Lines||LSK CD150+ CD48− HSCs|
|Incubation Time||24 h|
|Results||As expected, MycmRNAwas reduced by twofold to threefold compared with mock-treated HSCs in both groups, while there was no difference in Myc expression between the Erg+/− and Erg+/+ groups|
|Cell lines||2 PBMC cultures from healthy donors and 9 MCL cell lines (Granta-519, JVM-2, UPN1, Z-138, JeKo-1, ZBR, JBR, Mino, REC-1 cells)|
|Preparation method||Incubating MCL primary cells and cell lines as indicated with lenalidomide and/or CPI203. Adding MTT for 2-6 additional hours before spectrophotometric measurement. Each measurement is made in triplicate. Using untreated control cells to represent values . The GI50 is calculated as the concentration that produced 50 % growth inhibition. Using the Calcusyn software version 2.0 to calculate Combination indexes (CIs) . When CI <1 ,the interaction between two drugs is considered synergistic.|
|Incubation time||72 hours|
|Animal models||REC-1 tumor-bearing mice|
|Dosages||2.5 mg/kg twice daily|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Synergistic antitumor activity of lenalidomide with the BET bromodomain inhibitor CPI203 in bortezomib-resistant mantle cell lymphoma.
Moros A, et al. Leukemia. 2014 Mar 18. PMID: 24721791.
BRD4 is an atypical kinase that phosphorylates serine2 of the RNA polymerase II carboxy-terminal domain.
Devaiah BN, et al. Proc Natl Acad Sci U S A. 2012 May 1;109(18):6927-32. PMID: 22509028.
|Related Epigenetic Reader Domain Products|
CPI-637 is a potent and selective CBP/EP300 bromodomains inhibitor with IC50 of 0.03±0.01μM and 11.0±0.6 μM for CBP/EP300 and BRD4, respectively.
GSK1324726A (I-BET726) is a highly selective inhibitor of BET family proteins with IC50 of 41 nM, 31 nM, and 22 nM for BRD2, BRD3, and BRD4, respectively.
PFI-3 is a selective chemical probe for SMARCA bromodomains, including SMARCA2, SMARCA4 and PB1(5) bromodomains with a Kd of 89 nM.
SGC-CBP30 is a potent CREBBP/EP300 inhibitor with IC50 of 21 nM and 38 nM in cell-free assays, respectively.
ARV-771 is a small-molecule pan-BET degrader with Kd values of 4.7, 7.6, 7.6 nM against BRD2, BRD3 and BRD4, respectively.
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