GNE-049

Research use only, not for human use.

GNE-049 (GNE049) is a potent, selective, orally available inhibitor of CBP/p300 bromodomain with biochemical IC50 of 1.1/2.3 nM, respectively.

GNE-049 (GNE049) is a potent, selective, orally available inhibitor of CBP/p300 bromodomain with biochemical IC50 of 1.1/2.3 nM, respectively; displays 3,850-fold selectivity over BRD4; shows excellent potency (12 nM) in a BRET cellular assay and inhibits the expression of MYC with EC50 of 14 nM in MV-4-11 cells; demonstrates significant dose-dependent inhibition of AR signaling and PC proliferation in vitro and in vivo.

GNE-049 is selected for further profiling as it has the best balance ofliver 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.

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 (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.

GNE049 | GNE 049

Chromatin/Epigenetic

Bromodomain

Bromodomain

——

——

1936421-41-8

510.59

C27H32F2N6O2

>98% (HPLC)

DMSO : 100 mg/mL 195.86 mM

CC(N1CCC(N(C2COCC2)N=C3N4CCCC5=C4C=C(C(F)F)C(C6=CN(C)N=C6)=C5)=C3C1)=O

1-(3-(7-(difluoromethyl)-6-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)-1-(tetrahydro-2H-pyran-4-yl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl)ethan-1-one

(-20℃)

With Ice Pack

≥ 2 years