JQ1

(+) -JQ-1 (JQ1) is a potent, selective, cell-permeable BET bromodomain inhibitor with IC50 of 77 nM/33 nM for BRD4 BD1 and BD2, respectively; induces rapid expression of keratin in treated NMC 797 cells, displaces the BRD4 fusion oncoprotein from chromatin, prompting squamous differentiation and specific antiproliferative effects in BRD4-dependent cell lines and patient-derived xenograft models. (In Vitro) : (+) -JQ-1 represents a potent, highly specific and Kac competitive inhibitor for the BET family of bromodomains. (+) -JQ-1 (100 nM, 48 h) prompts squamous differentiation exhibited by cell spindling, flattening and increased expression of keratin. (+) -JQ-1 (250 nM) induces rapid expression of keratin in treated NMC 797 cells compared to (-) -JQ1 (250 nM) and vehicle controls, as determined by quantitative immunohistochemistry. (+) -JQ-1 (250 nM) elicits a time-dependent induction of strong (3+) keratin staining of treated NMC 797 cells, compared to (-) -JQ1 (250 nM) . De-repression of autophagy genes is observed almost immediately after (+) -JQ-1 addition. (+) -JQ-1 is a potent thienodiazepine inhibitor (Kd=90 nM) of the BET family coactivator protein BRD4, which is implicated in the pathogenesis of cancer via transcriptional control of the MYC oncogene. Dose-ranging studies of (+) -JQ-1 demonstrates potent inhibition of H4Kac4 binding with a IC50 value of 10 nM for murine BRDT and 11 nM for human BRDT. (In Vivo) :Matched cohorts of mice with established tumors are randomized to treatment with (+) -JQ1 (50 mg/kg) or vehicle, administered by daily intraperitoneal injection. Prior to randomization, and after four days of therapy, mice are evaluated by FDG-PET imaging. A marked reduction in FDG uptake is observed with (+) -JQ1 treatment. Tumor-volume measurements confirm a reduction in tumor growth with JQ1 treatment. Pharmacokinetic studies of (+) -JQ1 are performed in CD1 mice following intravenous and oral administration. Mean plasma concentration-time profiles of (+) -JQ1 after intravenous dosing (5 mg/kg) . The pharmacokinetic parameters for intravenous (+) -JQ1 demonstrate excellent drug exposure (AUC=2090 hr*ng/mL) and an approximately one hour half-life (T1/2) . Mean plasma concentration-time profiles of (+) -JQ1 after oral dosing (10 mg/kg) . The pharmacokinetic parameters for oral (+) -JQ1 demonstrate excellent oral bioavailability (F=49%), peak plasma concentration (Cmax=1180 ng/mL) and drug exposure (AUC=2090 hr*ng/mL) .