BET Inhibitors & Oncology

Small molecule inhibition of BET proteins is an exciting new epigenetic approach to treat cancer. BET inhibitors (BETi) have shown promising preclinical efficacy in multiple cancer models, with clinical validation emerging as trials are completed. Our oncology program centers around developing best-in-class BETi for the treatment of cancers with significant unmet need. Zenith is the first and only company to show clinical proof of concept with a BET inhibitor in multiple solid tumors.

BETi target cancer in a fundamentally different way than most chemotherapeutic drugs and existing targeted therapies, including kinase inhibitors, hormone modulators, and immunotherapies. The body has evolved natural processes which defend against the unchecked growth of its cells, which limit proliferation and can initiate programed cell death – or apoptosis – when growth starts to get out of control.

A hallmark of cancer is the expression of “oncogenes” within tumor cells, which interfere with the normal checks on cell division and free tumors to grow rampant. BETi act by repressing expression of oncogenes, allowing the body’s natural checks and balances to retake control, inhibiting cell proliferation and inducing apoptotic cell death.

Oncogene expression in tumor cells is often driven by protein structures known as “super-enhancers”, which are formed to allow increased expression of specific sets of genes and include BET protein family members. By binding to the BRD2, BRD3, BRD4, and BRDT bromodomains, BETi prevent super-enhancers from forming and the subsequent expression of oncogenes. In this fashion, BETi specifically target super-enhancer driven overexpression in tumor cells over normal cellular processes.