ZEN-3694 is an orally bioavailable small molecule discovered and developed from a BET bromodomain inhibitor discovery platform. In vitro, ZEN-3694 selectively binds to both bromodomains of the BET proteins, inhibiting the interaction of acetylated histone peptide with IC50 values in low nM range. ZEN-3694 inhibits proliferation of MV4-11 AML cells with an IC50 of 0.2 uM, and inhibits MYC mRNA expression with an IC50 of 0.16 uM.

ZEN-3694 has also demonstrated strong activity against many solid tumor and hematological cell lines with sub-uM IC50 values. In vitro synergy with Standard of Care (SOC) agents has been shown in a wide variety of malignancies including Breast, Prostate, Lung, Melanoma, AML, and DLBCL. Xenograft studies conducted with ZEN-3694 in AML, prostate and breast cancer models have demonstrated that it is efficacious at well-tolerated doses, modulating target gene expression and halting tumor growth in a dose-dependent manner.

In the AR positive VCAP prostate cancer cell line, ZEN-3694 inhibits proliferation synergistically with the AR antagonists enzalutamide and ARN-509. In an in vitro enzalutamide resistance model characterized by the up-regulation of the glucocorticoid receptor (GR), GR expression was inhibited by ZEN-3694 in a dose-dependent manner. Sensitivity to ZEN-3694 was unaltered, suggesting that it could be a valid therapeutic approach in patients developing resistance to AR antagonists through GR induction.

Robust PD modulation has been observed across multiple matrices for ZEN-3694 and will be explored further in the clinic. Promising target validation data, excellent pharmacological properties, and robust activity of ZEN-3694 across a variety of hematological malignancy and solid tumor settings support the clinical development of ZEN-3694 in various oncologic indications.

Citation Format: Sarah Attwell, Eric Campeau, Ravi Jahagirdar, Olesya Kharenko, Karen Norek, Laura Tsujikawa, Cyrus Calosing, Reena Patel, Emily Gesner, Sanjay Lakhotia, Henrik Hansen. The clinical candidate ZEN-3694, a novel BET bromodomain inhibitor, is efficacious in the treatment of a variety of solid tumor and hematological malignancies, alone or in combination with several standard of care and targeted therapies. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C86.