Small molecule inhibition of BET bromodomain containing proteins is an exciting new epigenetic approach to treat cancer. BET bromodomain inhibitors have shown promising preclinical efficacy in multiple models of hematological malignancies and solid tumors and clinical validation is emerging. Our oncology program centers around developing best in class BET inhibitors for the treatment of cancers with significant unmet need.

BET bromodomain inhibitors are part of a novel and emerging class of epigenetic regulators that target cancer in a fundamentally different way than most chemotherapeutic drugs and existing targeted therapies, including kinase inhibitors, hormone modulators, and immunotherapies. BET inhibitors   act by repressing expression of oncogenes, including MYC and BCL-2, that are aberrantly highly expressed in many cancer cells, resulting in inhibited cell proliferation and induction of apoptotic cell death.

Additionally, it has recently been shown that cancer progression can be driven by tumor cells acquiring super-enhancers to overexpress certain hallmark oncogenes. BET inhibitors selectively suppress super-enhancer driven gene expression, and have shown selectivity towards tumor cells. BET proteins also play a central role in the transcriptional program of oncogenes driven by gene fusions, translocations and mutations. 

Drug resistance is a critical limitation across all therapeutic modalities and there is a broad preclinical dataset demonstrating that the treatment of these resistant cancers with BET inhibitors renders them sensitive to the various therapies. This offers significant clinical potential for the treatment of resistant cancers with BET inhbitors.

The novel mechanisms of action of BET inhibitors through various transcriptional programs involved in cancer and the resistance to standard of care therapy form a natural basis for patient pre-selection and efficient clinical development. Restoration of androgen receptor (AR) signaling is a hallmark of castration-resistant prostate cancer (CRPC), and ZEN-3694 was shown to inhibit AR signaling in several pre-clinical models of CRPC, both in vitro and in vivo, including models of resistance to the AR antagonist enzalutamide. Zenith has entered a phase I clinical study for its lead compound ZEN-3694 in mCRPC patients progressing after enzalutamide and/or abiraterone therapy. The trial includes a rich translational biology plan to assess patient’s response, as well as identify potential predictive biomarkers of response. Circulating tumor cell (CTC) enumeration and tumor biopsies through the dose expansion phase will be used to measure disease progression, and characterize the transcriptional landscape of resistance and activated oncogenic pathways in order to establish putative correlations with patient’s responses. Furthermore, Zenith developed a robust whole blood assay to measure the activity of ZEN-3694 in patients during the dose escalation and expansion phases of clinical trials. This enables the gathering of relevant information about the physiological properties and activities of ZEN-3694 in humans. It also determines potential biomarkers to identify future patients with greater chances of benefit from a therapy including ZEN-3694.