Prostate cancer is primarily driven by an activated 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.
Currently approved antiandrogen treatments suppress AR activity by interfering with the production of androgens or preventing androgens from binding to the LBD. Over time, resistance develops at the DNA level (AR amplification; AR deletions, insertions, truncations and mutations) or RNA level (emergence of AR splice variants), resulting in a reactivated AR and disease progression.
EPI-7386 inhibits AR activity with a unique mechanism of action by binding to the AR NTD to disrupt AR gene transcription
Unlike other therapies, ESSA’s first-in-class Anitens suppress AR activity by inhibiting the AR NTD, suppressing AR biology independent of the LBD.
Preclinically, EPI-7386 can inhibit both full-length and clinically relevant mutant and splice variant forms of AR, including forms of AR that are resistant to current antiandrogen treatments. ESSA’s novel approach has the potential to prevent or delay drug resistance, in addition to broadly inhibiting AR activity in earlier stages of disease.
ANITAC™ AR NTD Degraders
Leveraging ESSA’s scientific foundation in successfully targeting the N-terminal domain of the androgen receptor with a new class of small molecules called Anitens, ESSA is developing the first generation of ANITen bAsed Chimera (ANITAC™) degraders targeting the AR NTD. In preclinical models, the orally bioavailable ANITAC degraders can eliminate forms of AR protein found in castration-resistant prostate cancer that can potentially drive disease progression, including LBD mutants and LBD truncated splice variants.
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.
