GNE-049 (C09-1135-564)

GNE-049 is a highly potent and selective CBP inhibitor with an IC 50 of 1.1 nM in TR-FRET assay. GNE-049 also inhibits BRET and BRD4(1) with IC 50 s of 12 nM and 4200 nM, respectivelyIn VitroGNE-049 is selected for further profiling as it has the best balance of liver microsomes (LM) stability, selectivity, and cellular potency GNE-049 has excellent potency in the BRET cellular assay and, in an orthogonal measure of the target engagement, GNE-049 is shown to inhibit the expression of MYC (MV4-11 cell line) with an EC 50 of 14 nM. MCE has not independently confirmed the accuracy of these methods. They are for reference only.In VivoGNE-049 demonstrates acceptable PK in mouse, rat, dog, and monkey. Determination of potency versus a selection of bromodomains revealed that GNE-049 is selective for CBP/P300 and, importantly, quite selective (3820-fold) over BRD4(1). GNE-049 is further evaluated in a rat single dose (30-250 mg/kg QD) toxicokinetic study. Adverse central nervous system (CNS)-related signs (e.g., marked hyperactivity and vocalization) are observed in several of the rats at the 250 mg/kg dose level. Furthermore, at the 250 mg/kg dose level, the ratio of the unbound drug concentration in brain to unbound drug concentration in plasma (K p,uu ) 3 h post dose is determined to be 0.43, indicating that GNE-049 is penetrating into the CNS and potentially resulting in the observed toxicity . MCE has not independently confirmed the accuracy of these methods. They are for reference only.Form:SolidIC50& Target:IC50: 1.1 nM (CBP), 12 nM (BRET), 4200 nM (BRD4(1)). Specification: 0.98 Molecular Formula: C27H32F2N6O2 Molecular Weight: 510.58 PubChem CID: 121373418 Isomeric SMILES: CC(=O)N1CCC2=C(C1)C(=NN2C3CCOCC3)N4CCCC5=CC(=C(C=C54)C(F)F)C6=CN(N=C6)C