An oral androgen receptor PROTAC degrader for prostate cancer.

Authors

null

Taavi Neklesa

Arvinas, New Haven, CT

Taavi Neklesa , Lawrence B Snyder , Ryan R Willard , Nicholas Vitale , Kanak Raina , Jennifer Pizzano , Deborah A Gordon , Mark Bookbinder , Jennifer Macaluso , Hanqing Dong , Zheng Liu , Caterina Ferraro , Gan Wang , Jing Wang , Craig M Crews , John Houston , Andrew P Crew , Ian Taylor

Organizations

Arvinas, New Haven, CT, Yale University, New Haven, CT

Research Funding

Pharmaceutical/Biotech Company

Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC that leads to ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, DMPK, toxicology and preclinical efficacy studies. Results: This AR PROTAC completely degrades AR in all cell lines tested, with an observed 50% degradation concentration (DC50) < 1 nM. PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces potent apoptosis in VCaP cells. The AR PROTAC degrades all clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling can be achieved in both an intact and castrate setting. Further, the AR PROTAC demonstrates in vivo efficacy and reduction of oncogenic Erg protein in a long term, castrate, enzalutamide-resistant VCaP tumor model. DMPK and exploratory toxicology studies show robust oral, dose proportional drug exposure in rodent and non-rodent species. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader that demonstrates efficacy in enzalutamide-resistant prostate cancer.

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Abstract Details

Meeting

2018 Genitourinary Cancers Symposium

Session Type

Poster Session

Session Title

Poster Session B: Prostate Cancer, Urothelial Carcinoma, and Penile, Urethral, and Testicular Cancers

Track

Urothelial Carcinoma,Prostate Cancer,Penile, Urethral, and Testicular Cancers

Sub Track

Prostate Cancer - Advanced Disease

Citation

J Clin Oncol 36, 2018 (suppl 6S; abstr 381)

DOI

10.1200/JCO.2018.36.6_suppl.381

Abstract #

381

Poster Bd #

F6

Abstract Disclosures