GNE-049 是一种高效的选择性 CBP 抑制剂，在 TR-FRET 实验中 IC₅₀ 为 1.1 nM。GNE-049 还抑制 BRET 和 BRD4(1)，IC₅₀ 分别为 12 nM 和 4200 nM。

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, respectively.

Solid

IC50: 1.1 nM (CBP), 12 nM (BRET), 4200 nM (BRD4(1))

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. has not independently confirmed the accuracy of these methods. They are for reference only.

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. has not independently confirmed the accuracy of

Room temperature in continental US; may vary elsewhere.

-20°C, stored under nitrogen In solvent : -80°C, 6 months; -20°C, 1 month (stored under nitrogen)

[1]. Romero FA, et al. GNE-781, A Highly Advanced Potent and Selective Bromodomain Inhibitor of Cyclic Adenosine Monophosphate Response Element Binding Protein, Binding Protein (CBP). J Med Chem. 2017 Nov 22;60(22):9162-9183.

In Vitro: DMSO : 100 mg/mL (195.86 mM; Need ultrasonic)配制储备液