BET bromodomain inhibitor 1

BET bromodomain inhibitor 1 is an orally active, selective bromodomain and extra-terminal (BET) bromodomain inhibitor with an IC 50 of 2.6 nM for BRD4 . BET bromodomain inhibitor 1 binds to BRD2(2), BRD3(2), BRD4(1), BRD4(2), and BRDT(2) with high affinities ( K d values of 1.3 nM, 1.0 nM, 3.0 nM, 1.6 nM, 2.1 nM, respectively). bromodomain inhibitor 1 has anti-cancer activity In Vitro BET bromodomain inhibitor 1 (compound 38; 31.25-125 nM; 24 hours) leads to more pronounced G1-phase cell cycle arrest. BET bromodomain inhibitor 1 (31.25-500 nM; 6 or 24 hours) is highly effective in inducing dose-dependent inhibition on c-Myc expression and upregulation of p21 levels. BET bromodomain inhibitor 1 (31.25-125 nM; 6 hours) robustly reduces the expressions of c-Myc, BCL-2, and CDK6. BET bromodomain inhibitor 1 does not inhibit five cytochrome P450 enzymes (IC 50 >20 μM). BET bromodomain inhibitor 1 demonstrates an excellent selectivity for the BET bromodomain family over other bromodomains, with an ∼1500-fold selectivity for BRD4(1) over EP300 (IC 50 =3857 nM). BET bromodomain inhibitor 1 strongly inhibited the growth of acute myeloid leukemia cell line MV4-11, acute leukemia cell lines Kasumi-1 and RS-4-11, and multiple myeloma cancer cell line MM1.S cells with IC 50 values of 2.4, 4.8, 17.6 and 15.1 nM, respectively. MCE has not independently confirmed the accuracy of these methods. They are for reference only. Cell Cycle AnalysisCell Line: MV-4-11 cells Concentration: 31.25, 62.5, 125 nM Incubation Time: 24 hours Result: Led to more pronounced G1-phase cell cycle arrest. Western Blot AnalysisCell Line: MV-4-11 cells Concentration: 31.25, 62.5, 125, 250, 500 nM Incubation Time: 6 or 24 hours Result: Induced dose-dependent inhibition on c-Myc expression and upregulation of p21 levels. RT-PCRCell Line: MV-4-11 cells Concentration: 31.25, 62.5, 125 nM Incubation Time: 6 hours Result: Robustly reduced the expressions of c-Myc, BCL-2, and CDK6. In Vivo BET bromodomain inhibitor 1 (compound 38; 6.25, 12.5 mg/kg; PO; daily ; for 28 days) exhibits stronger antitumor activities and completely inhibits the growth of tumor with a tumor growth inhibition (TGI) of 99.7% at 12.5 mg/kg . BET bromodomain inhibitor 1 (1 mg/kg; IV) has a T 1/2 of 1.3 and 0.9 hours, a CL of 21.5 and 15.3 mL/min•kg, and a V ss of 1464 and 782 mL/kg for rats and mouse, respectively . BET bromodomain inhibitor 1 (3 mg/kg; PO) has a T 1/2 of 3.6 hours, a C max of 159 ng/mL and an AUC of 884 ng•h/mL for rats . BET bromodomain inhibitor 1 (1.3 mg/kg; PO) has a T 1/2 of 1.3 hours, a C max of 399 ng/mL and an AUC of 1710 ng•h/mL for mouse . MCE has not independently confirmed the accuracy of these methods. They are for reference only. Animal Model: An MV4-11 mouse xenograft model Dosage: 6.25, 12.5 mg/kg Administration: PO; daily ; for 28 days Result: Exhibited stronger antitumor activities and completely inhibited the growth of tumor with a tumor growth inhibition (TGI) of 99.7% at 12.5 mg/kg. Animal Model: Male SD rats Dosage: 1 mg/kg (Pharmacokinetic Analysis) Administration: IV Result: Had a T 1/2 of 1.3 hours, a CL of 21.5 mL/min•kg, and a V ss of 1464 mL/kg. Form:Solid IC50& Target:BRD4 2.6 nM (IC 50 ) BRD2(2) 1.3 nM (Kd) BRD3(2) 1.0 nM (Kd) BRD4(1) 3.0 nM (Kd) BRD4(2) 1.6 nM (Kd) BRDT(2) 2.1 nM (Kd)

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