GNE-049

GNE-049 is a highly potent and selective CBP inhibitor with an IC₅₀ of 1.1 nM in TR-FRET assay. GNE-049 also inhibits BRET and BRD4(1) with IC₅₀s of 12 nM and 4200 nM, respectively^[1]. IC50 & Target: IC50: 1.1 nM (CBP), 12 nM (BRET), 4200 nM (BRD4(1))^[1] In Vitro: GNE-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 EC₅₀ of 14 nM^[1]. In Vivo: GNE-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^[1].