Development of small molecule therapeutics targeting AR-V7 for prostate cancer

Abstract
Prostate cancer is the second most commonly diagnosed cancer in men in the U.S. About 250,00 cases and
34,000 deaths from prostate cancer occur each year, making it the leading cause of cancer-related deaths in
U.S. men. Incidence is so high that approximately one in every eight men will be diagnosed with the disease
over their lifetimes, and there are currently an estimated 3.2 million men living with prostate cancer in the U.S.
Due to this high incidence, prostate cancer creates a significant economic burden estimated to total over $13
billion in the U.S. annually. It is well established that androgen signaling drives prostate cancer growth and
metastasis. Thus, androgen deprivation therapy, which inhibits androgen receptor (AR) signaling, is widely used
as first-line therapy for advanced and metastatic prostate cancer. However, the majority of patients progress,
with lethal metastatic castration-resistant prostate cancer (mCRPC). Interestingly, despite androgen deprivation,
mCRPC continues to be driven by AR signaling due to the presence of AR splice variants that are constitutively
active in the nucleus. ARMA Bio is developing dual inhibitors of AR-full length (AR-fl) and AR-V7, the most
prevalent splice variant of the androgen receptor in men with mCRPC. AR-V7 expression in patients with mCRPC
is associated with drug resistance and poor survival outcomes. Currently there is no dual AR-fl/AR-V7 inhibitor
on the market, leaving patients with mCRPC with no therapeutic options. A first-in-class dual inhibitor has the
potential to overcome drug resistance, synergize with conventional androgen receptor therapy, and offer a much-
needed therapeutic option for men with mCRPC, ultimately improving clinical outcomes. In this Fast Track
project, ARMA proposes to 1) Perform medicinal chemistry for compound optimization and assess selectivity,
potency, and mechanism of action. 2) Investigate in vivo toxicity and pharmacokinetics. 3) Evaluate efficacy of
lead candidate in mCRPC xenografts. 4) Assess efficacy and synergism with enzalutamide in additional models
including patient-derived xenografts. 5) Perform mechanistic studies as a foundation for clinical biomarker
development. 6) Perform GLP manufacturing and IND-enabling toxicology studies. Ultimately, this work will
identify a lead compound and provide proof-of-principle data to advance the goal of developing a first-in-class
pharmacologic inhibitor of AR-fl/AR-V7. This inhibitor could be readily combined with existing anti-androgen
receptor treatments to not only reverse, but also prevent, the onset of AR-V7-mediated drug resistance, thereby
benefiting patients with earlier stages of disease.

Grant Number: 4R44CA290913-02
NIH Institute/Center: NIH
Principal Investigator: Cheuk Man Cherie Au