Target nature :
Bromodomain and extra-terminal (BET) bromodomains proteins with a 475-fold selectivity for the second bromodomain of the BRD3 protein (BRD3-BDII) over its first bromodomain (BRD3-BDI)
CAS n° :
Not available yet
Mecanism of action :
CRCM5484 is a competitive inhibitor of acetylated-lysines in the cavity of BET bromodomains. Prevent protein/protein interactions between bromodomains and peptides bearing acetylated lysins with a selectivity for BRD3-BDII vs BRD3-BDI.
Physico-chemical properties :
Solubility (PBS pH 7.4) = 6 µM
Solubility (DPBS pH 7.4, 1% DMSO) = 77 µM
Probe availability :
Powder available on the HiTS platform upon request
Princeps reference :
Carrasco K, Montersino C, Derviaux C, Saez-Ayala M, Hoffer L, Restouin A, Castellano R, Casassa J, Roche P, Pasquier E, Combes S, Morelli X, Collette Y, Betzi S. CRCM5484: A BET-BDII Selective Compound with Differential Anti-leukemic Drug Modulation. J Med Chem. 2022 Apr 14;65(7):5660-5674. doi: 10.1021/acs.jmedchem.1c02168. Epub 2022 Mar 29. PMID: 35348328.
More bibliography :
Other available information on the probe :
Powder and solutions in DMSO (10 mM) at -20 degrees.
Other information on the target :
NA
Selectivity profile :
The affinity and the selectivity of CRCM5484 were confirmed by two experiments: an HTRF selectivity assay on the six BDs of the BET family and a BROMOscan assay on the whole BD family tree (DiscoverX-Eurofins). CRCM5484 exhibits a BDII-selective profile (HTRF assay) with IC50 values of 130, 20, and 71 nM for the BDIIs and 1300, 9500, and 4700 nM for the BDIs of BRD4, BDR3, and BRD2, respectively. The BROMOscan evaluation at 1 ¿M confirmed the BDII selectivity profile and also an overall BET family selectivity across the 32 evaluated domains.
In vivo data :
CRCM5484 is well tolerated by mice at 50mg/kg (intraperitoneal route to 7 weeks-old male Swiss mice by unique injection).
In vitro data :
CRCM5484 exhibits a BDII-selective profile (HTRF assay) with IC50 values of 130, 20, and 71 nM for the BDIIs and 1300, 9500, and 4700 nM for the BDIs of BRD4, BDR3, and BRD2, respectively. The affinity for BRD3-BDII was confirmed by ITC with a 150 nM measured KD. The BROMOscan evaluation at 1 ¿M confirmed the BDII selectivity profile and also an overall BET family selectivity across the 32 evaluated domains. CRCM5484 exhibits similar in vitro and in cellular activity to the most BDII-selective compounds described in the literature. Moreover, a drug sensitivity response profile (DSRP) in a combination screen of CRCM5484 with 78 pharmacological agents pinpointed that CRCM5484 could potentiate the antiproliferative activity of certain drugs in patient-derived leukemia cells.
Toxicity :
CRCM5484 is well tolerated by mice at 50mg/kg (intraperitoneal route to 7 weeks-old male Swiss mice by unique injection).
Chaine SMILES :
CC(=O)N1CCc4c(C1)sc5nc(SCC(=O)Nc2cccnc2C)n(Cc3ccco3)c(=O)c45
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