GNE-049 is a highly selective and potent inhibitor designed to target the CREB-binding protein (CBP) with high affinity, exhibiting an IC50 of 1.1 nM for the suppression of BRET and BRD4 activity, which consequently blocks prostate cancer cell proliferation in both in vitro and in vivo models.

MV4-11 cells:14 nM (EC50), HEK-293 cells:15 nM

GNE-049 performs well in BRET cell assays and, in an orthogonal targeted assay, inhibits MYC expression (MV4-11 cell line) with an EC50 of 14 nM.[1]
CBPD-409 induced strong degradation of CBP/p300 by DC 500.2-0.4 nM and exhibited strong antiproliferative effects with IC50 of 1.2-2.0 nM in VCaP, LNCaP, and 22Rv1 AR+ prostate cancer cell lines. [2]

GNE-049 shows acceptable PK in mouse, rat, dog, and monkey. GNE-049 is further evaluated in a rat single dose (30-250 mg/kg QD) toxicokinetic study. GNE-049 is selective for CBP/P300 and, importantly, quite selective (3820-fold) over BRD4(1), which revealed from the Determination of potency versus a selection of bromodomains. Furthermore, at the 250 mg/kg dose level, the ratio of the unbound drug concentration in the brain to unbound drug concentration in plasma (Kp,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.