Inhibiting BET Bromodomain Proteins with OTX015: A Promising Therapeutic Approach for Cancer Treatment

The BET bromodomain proteins, such as BRD2, BRD3, and BRD4, are significant regulators of cell processes and have been implicated in various diseases including cancer. OTX015, a novel compound, has been identified as an inhibitor of these proteins, showing potential in both in vitro and in vivo tumor models.

OTX015 was tested for its binding affinity to BRD2, BRD3, and BRD4 using a time-resolved fluorescence resonance energy transfer (TR-FRET) assay. It demonstrated potent inhibition with EC50 values ranging from 10 to 19 nM, indicating competitive binding. The compound also effectively inhibited the interaction between these bromodomain proteins and acetylated histone H4 (AcH4) with IC50 values between 92 and 112 nM.

In assessing the effects on cancer cell proliferation, OTX015 displayed antiproliferative activity against a range of human cancer cell lines, with GI50 values for most hematologic malignancies between 60 and 200 nM. In vivo studies in mice with Ty82 BRD-NUT midline carcinoma xenografts showed that oral administration of OTX015 significantly reduced tumor growth, with tumor growth inhibition (TGI) of 79% at a dosage of 100 mg/kg once daily and 61% at 10 mg/kg twice daily.

The study concludes that OTX015 is a potent inhibitor of BET bromodomain proteins and has shown significant anti-tumor effects in both cell and animal models. These results support the ongoing clinical development of OTX015, which is currently in Phase 1 trials for patients with advanced hematologic malignancies.