(+)-JQ1represents a potent, highly specific and Kac competitive inhibitor for the BET family of bromodomains. (+)-JQ1 (100 nM, 48 h) prompts squamous differentiation exhibited by cell spindling, flattening and increased expression of keratin. (+)-JQ1 (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.(+)-JQ1 (250 nM) elicits a time-dependent induction of strong (3+) keratin staining of treated NMC 797 cells, compared to (-)-JQ1 (250 nM). (+)-JQ1 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 (+)-JQ1 demonstrates potent inhibition of H4Kac4 binding with a IC50 value of 10 nM for murine BRDT(1) and 11 nM for human BRDT(1).
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).