BET bromodomain inhibitor 1 is an orally active, selective inhibitor of bromodomain and extra-terminal (BET) proteins. It specifically inhibits BRD4 with an IC50 of 2.6 nM. Additionally, BET bromodomain inhibitor 1 demonstrates high affinities towards BRD2(2), BRD3(2), BRD4(1), BRD4(2), and BRDT(2) with Kd values of 1.3 nM, 1.0 nM, 3.0 nM, 1.6 nM, and 2.1 nM, respectively. This compound exhibits anti-cancer activity.

BET bromodomain inhibitor 1 (compound 38; concentration range 31.25-125 nM; incubated for 24 hours) significantly induces G1-phase cell cycle arrest. At concentrations between 31.25-500 nM for 6 or 24 hours, it effectively triggers dose-dependent inhibition of c-Myc expression and increases p21 levels. A similar dose range over 6 hours markedly decreases the expressions of c-Myc, BCL-2, and CDK6. Notably, this inhibitor does not affect five cytochrome P450 enzymes (IC 50 >20 μM) and exhibits remarkable specificity for the BET bromodomain family, being approximately 1500 times more selective for BRD4(1) compared to EP300 (IC 50 =3857 nM). Furthermore, it potently suppresses the growth of several cancer cell lines, including acute myeloid leukemia (MV4-11), acute leukemia (Kasumi-1 and RS-4-11), and multiple myeloma (MM1.S), with IC 50 values of 2.4, 4.8, 17.6, and 15.1 nM, respectively. Detailed assessments through cell cycle analysis, Western blot, and RT-PCR in MV-4-11 cells corroborate these findings, highlighting its pronounced effect on G1-phase arrest, and the reduction of key oncogenic proteins and cell cycle regulators.

BET bromodomain inhibitor 1, when administered orally at doses of 6.25 and 12.5 mg/kg daily for 28 days, demonstrated significantly enhanced antitumor efficacy, completely suppressing tumor growth with a tumor growth inhibition (TGI) rate of 99.7% at 12.5 mg/kg in an MV4-11 mouse xenograft model. Pharmacokinetic studies show that at a dose of 1 mg/kg intravenously in male SD rats, this inhibitor had a half-life (T 1/2) of 1.3 hours, a clearance rate (CL) of 21.5 mL/min/kg, and a steady-state volume of distribution (V ss) of 1464 mL/kg. Moreover, when given orally at 3 mg/kg in rats, the compound had a T 1/2 of 3.6 hours, reached a maximum concentration (C max) of 159 ng/mL, and had an area under the curve (AUC) of 884 ng·h/mL; while at a dose of 1.3 mg/kg orally in mice, it exhibited a T 1/2 of 1.3 hours, a C max of 399 ng/mL, and an AUC of 1710 ng·h/mL.