BET bromodomain inhibitor 1 是一种具有口服活性的，选择性 BET 溴结构域抑制剂，对 BRD4 的 IC50 为 2.6 nM。BET bromodomain inhibitor 1 与 BRD2(2)，BRD3(2)，BRD4(1)，BRD4(2) 和 BRDT(2) 高亲和力结合 (Kd 值分别为 1.3 nM、1.0 nM、3.0 nM、1.6 nM、2.1 nM)。BET bromodomain inhibitor 1 具有抗癌活性。
BET bromodomain inhibitor 1 is an orally active, selective bromodomain and extra-terminal (BET) bromodomain inhibitor with an IC50 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 (Kd 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[1].
BET bromodomain inhibitor 1 (compound 38; 31.25-125 nM; 24 hours) leads to more pronounced G1-phase cell cycle arrest[1]. 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[1]. BET bromodomain inhibitor 1 (31.25-125 nM; 6 hours) robustly reduces the expressions of c-Myc, BCL-2, and CDK6[1]. BET bromodomain inhibitor 1 does not inhibit five cytochrome P450 enzymes (IC50>20 μM)[1]. 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 (IC50=3857 nM)[1]. 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 IC50 values of 2.4, 4.8, 17.6 and 15.1 nM, respectively[1].
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[1]. BET bromodomain inhibitor 1 (1 mg/kg; IV) has a T1/2 of 1.3 and 0.9 hours, a CL of 21.5 and 15.3 mL/min?kg, and a Vss of 1464 and 782 mL/kg for rats and mouse, respectively[1]. BET bromodomain inhibitor 1 (3 mg/kg; PO) has a T1/2 of 3.6 hours, a Cmax of 159 ng/mL and an AUC of 884 ng?h/mL for rats[1]. BET bromodomain inhibitor 1 (1.3 mg/kg; PO) has a T1/2 of 1.3 hours, a Cmax of 399 ng/mL and an AUC of 1710 ng?h/mL for mouse[1].
[1]. Zizhou Li, et al. Discovery of 8-Methyl-pyrrolo[1,2- a]pyrazin-1(2 H)-one Derivatives as Highly Potent and Selective Bromodomain and Extra-Terminal (BET) Bromodomain Inhibitors. J Med Chem. 2020 Apr 23;63(8):3956-3975.
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