GNE-272

GNE-272 is a potent and selective CBP/EP300 inhibitor with IC₅₀ 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^[1]. IC50 & Target: IC50: 0.02 μM (CBP), 0.03 μM (EP300), 13 μM (BRD4)^[1] 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 EC₅₀ of 0.91 μM and good correlation between the BRET and MYC cellular assays is observed^[1]. 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^[1].