Prostate cancer is predominantly driven by the androgen receptor (AR). The AR is composed of three domains: the ligand-binding domain (LBD) which binds to androgen hormones, the DNA-binding domain which binds to DNA in cells, and the N-terminal domain (NTD) which is necessary for AR gene transcription.
An activated AR is required for the growth and survival of most prostate cancer. Generally, there are three means of activating the AR.
Currently approved antiandrogen treatments are functional against the first mechanism by either interfering with the production of androgens or preventing androgens from binding to the LBD. Over time, these approaches eventually fail due to mechanisms of resistance which involve the LBD, whether at the DNA level (AR amplification, AR deletions, insertions, truncations and mutations) or RNA level (emergence of AR splice variants), allowing the androgen receptor signaling to remain active.
Designed to disrupt AR signaling in a novel way, EPI-7386 prevents AR transcriptional activity by binding to the NTD of the AR.
ESSA’s novel approach to AR inhibition targets the NTD of the AR, an area that is required for the transcriptional activity of the AR. By blocking the NTD, EPI-7386 inhibits AR-driven gene transcription and bypasses resistance mechanisms that may occur to current antiandrogen therapies.
Unlike current antiandrogen therapies which can only inhibit full-length AR, NTD inhibition of AR-directed biology occurs both in full-length AR and clinically relevant splice variant ARs. In this way, EPI-7386 has the potential to inhibit full-length AR as well as mutated and splice variant forms of the AR. Through this novel method of inhibiting the AR, EPI-7386 may be able to more broadly inhibit AR-driven biology.
AR is activated by androgen binding to the LBD which induces the dimerization and nuclear translocation of the AR. Activated AR then regulates the expression of genes involved in prostate cancer progression.
Current AR-targeted therapies work directly or indirectly through the LBD of the AR
Anitens target the NTD of the AR and can inhibit AR transcriptional activity
Anitens are active against AR forms missing the LBD and therefore, can bypass many resistance mechanisms to current AR-targeted therapies.
