BI-9564 is a selective inhibitor of BRD9 and BRD7 bromodomains (Kds = 14.1 and 239 nM; IC50s = 75 nM and 3.4 μM, respectively) that demonstrates cellular activity by semi-quantitative FRAP assay with ~90% inhibition of BRD9 and BRD7 at 0.1 μM and 1 μM, respectively. It does not bind to other bromodomain-containing BET family members (IC50s >100 μM as assessed by AlphaScreen), kinases, or G protein-coupled receptors and shows off-target selectivity only to the CECR2 bromodomain in in vitro ITC assays (Kd = 258 nM), but not in cell-based assays at concentrations up to 1 μM. BI-9564 has been shown to inhibit the growth of EOL-1 AML cells both in vitro (EC50 = 800 nM) and in a disseminated mouse model of AML (180 mg/kg/day). See the Structural Genomics Consortium (SGC) website for more information.
BI-9564 is a selective inhibitor of BRD9 and BRD7 bromodomains. It also exhibits antitumor activity in AML xenograft model. BI 9564 can be used as an epigentic probe to study bromodomain biology.
bi-9564 was identified as a brd9/7 specific inhibitor via fragment-based screening and structure-guided design. bi-9564 was found to be bind to brd9 with a higher affinity than to brd7, and was negative on bet family proteins. in addition, bi-9564 demonstrated in vitro off-target selectivity to cecr2, but not in cells [1].
in animal study, bomtac:nmrifoxn1nu mice were given two oral doses daily and the concentration of bi-9564 in plasma was measured. dose-dependent aucs were obtained for bi-9564, achieving exposures that were higher compared to the ec50 level for eol-1 cells. moreover, when the oral treatment with bi-9564 at 180 mg/kg was initiated on day 5 and applied daily with an interruption at day 18 and 19, a significant reduction in tumour growth compared to controls was found on day 18 leading to a median tumour growth inhibition value of 52% [1].
75 nm and 3.4 μm for brd9 and brd7 bromodomains, respectively
[1] martin lj et al. structure-based design of an in vivo active selective brd9 inhibitor. j med chem. 2016 may 26;59(10):4462-75.
