Birabresib (OTX015)

Birabresib (OTX-015) is a potent bromodomain (BRD2/3/4) inhibitor with IC50s ranging from 92 to 112 nM.

Signaling Pathways >> Epigenetics >> Epigenetic Reader Domain

Research Areas >> Cancer

IC50: 92-112 nM (BRD2, BRD3, BRD4)[1]

Birabresib (OTX-015) (500 nM) exposure induces a strong decrease of BRD2, BRD4 and c-MYC and increase of HEXIM1 proteins, while BRD3 expression is unchanged. c-MYC, BRD2, BRD3, BRD4 and HEXIM1 mRNA levels do correlate however with viability following exposure to Birabresib (OTX-015). Sequential combinations of Birabresib (OTX-015) with other epigenetic modifying drugs, panobinostat and azacitidine have a synergic effect on growth of the KASUMI cell line[2]. Birabresib (OTX-015) (0.1, 1, 5 μM) treatment induces HIV-1 full-length transcripts and viral outgrowth in resting CD4+ T cells from infected individuals receiving suppressive antiretroviral therapy (ART), while exerting minimal toxicity and effects on T cell activation. Birabresib-mediated activation of HIV-1 involves an increase in CDK9 occupancy and RNAP II C-terminal domain (CTD) phosphorylation[3].

In MDA-MB-231 murine xenografts, tumor mass is significantly (p < 0.05) reduced by Birabresib (OTX-015) (50 mg/kg) with respect to vehicle-treated animals. Birabresib (OTX-015) in combination with 2 mg/kg everolimus shows more effective activity than Birabresib alone[4].

For the MTT assay, cells are seeded in 24-well plates at 1×106 per well and treated with Birabresib (OTX-015) (0.01 nM-10 μM) for 72 h. Cells are transferred to 96-well plates and incubated with 0.5 mg/mL 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) in the dark at 37°C for 4 h. Cells are then lysed with 25% sodium dodecyl sulfate (SDS) lysis buffer and absorbance is read at 570 nm using a Microplate Reader. Three independent experiments are run for each cell line and untreated cells are used as negative controls.

Mice are subcutaneously injected in the right flank with 10×106 MDA-MB-231 cells. When average tumor weight is appr 130 mg, mice are randomized (nine animals/group) to one of the following experimental groups: vehicle (for Birabresib (OTX-015), water, twice daily, oral; for everolimus vehicle, 5% Tween-80/5% polyethylene glycol 400, thrice weekly, intraperitoneal); 50 mg/kg Birabresib (OTX-015), twice daily, oral; 2 mg/kg everolimus, thrice weekly, intraperitoneal; 50 mg/kg Birabresib (OTX-015) + 2 mg/kg everolimus, according to the single agent dosing schedules. In the experiment with paclitaxel, mice are randomized (eight animals/group) to vehicle (cremophor:ethanol 1:1, then diluted 1:5 with saline; once weekly, intravenous) or 0.15 mg/kg paclitaxel, once weekly, intravenous. Mice are sacrified at the first sign of severe distress and tumors are collected. Tumor weight (1 mm3 = 1 mg) is determined using the formula d2 × D/2, where 'd' and 'D' are the minor and major diameters of the tumor in mm, respectively. Growth curves of each tumor are normalized with respect to volume at the start of treatment. The doubling time (Td) of each untreated tumor is calculated by exponential fit of the whole growth curve. Treatment efficacy is evaluated based on T/C%, absolute growth delay (AGD) and log cell kill (LCK) parameters. In T/C%, T and C are the mean tumor weight of treated and control groups, respectively.

[1]. J. Kay Noel, et al. Abstract C244: Development of the BET bromodomain inhibitor OTX015. Mol Cancer Ther November 2013 12; C244.

[2]. Marie-Magdelaine Coudé, et al. BET inhibitor OTX015 targets BRD2 and BRD4 and decreases c-MYC in acute leukemia cells. Oncotarget. 2015 Jul 10; 6(19): 17698–17712.

[3]. Lu P, et al. The BET inhibitor OTX015 reactivates latent HIV-1 through P-TEFb. Sci Rep. 2016 Apr 12;6:24100

[4]. Vázquez R, et al. The bromodomain inhibitor OTX015 (MK-8628) exerts anti-tumor activity in triple-negative breast cancer models as single agent and in combination with everolimus. Oncotarget. 2017 Jan 31;8(5):7598-7613.

(+)-JQ1 | GSK126 | Tazemetostat (EPZ-6438) | A 485 | Curcumin | ARV-771 | ARV-825 | I-BET762 | BI 2536 | GSK343 | C646 | 3-Deazaneplanocin A (hydrochloride) | I-BET151 | 666-15 | CPI-637