BAZ2-ICR

BAZ2A/B (bromodomain adjacent to zinc finger domain, 2A/B) is a member of the nuclear remodeling complex (NoRC), but little is known about the function. Elevated levels of BAZ2A expression are observed in prostate cancer. BAZ2-ICR is a dual BAZ2A and BAZ2B bromodomain small-molecule inhibitor. It displays moderate potency (BAZ2A, ITC Kd = 109 nM; IC50 = 130 nM; BAZ2B, ITC Kd = 170 nM; IC50 = 180 nM) and good selectivity against a broad panel of 47 bromodomains: 15-fold selectivity for binding BAZ2A/B over CECR2 and >100-fold selectivity over all other bromodomains. BAZ2-ICR displaces BAZ2 bromodomains in living cells as demonstrated by accelerated FRAP recovery at 1 µM in the BAZ2A-FRAP assay. (PK data: LogD = 1.05, solubility 25 mM (D2O), F = 70%.) In comparison with another BAZA/B small-molecule inhibitor (GSK2801), it displays a better selectivity. To assess the compound's activity in a model organism, further experiments are required.

In cells, the probe shows good selectivity, but the compound has only a moderate binding affinity ~100 nM and cellular activity (1 µM in FRAP assay). BAZ2-ICR has been shown by ITC to bind to BAZ2A with a KD of 109 nM and to BAZ2B with a KD of 170 nM. The compound has good selectivity; it only binds one off-target bromodomain: CECR2 (Kd= 1.55 μM). The compound (10 µM) displayed no activity against a panel of 55 receptors and ion channels. BAZ2-ICR shows good solubility, high stability in mouse microsomes and is cell permeable. BAZ2-ICR was tested in mouse model using iv and oral routes of administration (5 mg/kg); the compound showed good bioavailability (70%) and moderate clearance (∼50% of mouse liver blood flow). The maximum tolerated dose (MTD) was not determined. Considering the compound's cellular activity, a higher in vivo dose should be tested to see if concentration > 1µM could be maintained for longer time .

This probe has modest affinity to BZA2A (130 nM) and BZA2B (180 nM).  It has good selectivity against 45 other bromodomains with the exception of CERC2 against which BAZ2-ICR is only 10-15 fold selective. In a cellular FRAP assay, activity was observed at a concentration of 1 uM; however, only a single concentration was reported. In the absence of dose-response data, absolute potency cannot be established.