GNE-272 is a potent and selective CBP/EP300 inhibitor with IC 50 values of 0.02, 0.03 and 13 μM for CBP, EP300 and BRD4 , respectively. GNE-272 is also a selective in vivo probe for CBP/EP300
In Vitro
GNE-272 is exquisitely selective for CBP/ EP300 and remarkably selective (650-fold) over BRD4. When tested at 10 μM in 35 kinase panel and 42 receptors off-target screening panel, GNE-272 does not inhibit any target at >30%. In addition, GNE-272 does not inhibit (>10 μM, top concentration) several cytochrome P450s (3A4, 1A2, 2C9, 2C19, 2D6). The compound has good potency in the BRET cellular assay. In an orthogonal measure of the target engagement, GNE-272 is shown to inhibit the expression of MYC10 (MV4−11 cell line) with an EC 50 of 0.91 μM and good correlation between the BRET and MYC cellular assays is observed. MCE has not independently confirmed the accuracy of these methods. They are for reference only.
In Vivo
GNE-272 demonstrates low clearance following a 1 mg/ kg intravenous dose in a mouse PK experiment and good oral bioavailability when dosed at 100 mg/kg, reaching an unbound C max of 26 μM. GNE-272 shows a marked antiproliferative effect in hematologic cancer cell lines and modulates MYC expression in vivo that corresponds with antitumor activity in an AML tumor model . MCE has not independently confirmed the accuracy of these methods. They are for reference only.
