Arvinas' PROTAC® Discovery Engine

Arvinas aims to treat cancer and neurological disorders by specifically targeting disease-driving proteins for degradation by the ubiquitin-proteasome system using PROteolysis-TArgeting Chimeras (PROTAC® protein degraders). A PROTAC protein degrader is a bifunctional small molecule that recruits a specific ubiquitin ligase (E3) to a target protein of interest, thereby inducing proteasome-mediated degradation of the ubiquitin-modified target. ARV-110, a PROTAC protein degrader that drives androgen receptor degradation, is currently being evaluated in clinical trials for treatment of metastatic, castration-resistant prostate cancer. The estrogen receptor (ER)-targeting PROTAC protein degrader ARV-471 is being evaluated for treatment of ER+ locally advanced or metastatic breast cancer. Preclinical and early clinical data for these two programs will be presented. Our PROTAC discovery engine is also being employed to develop a robust pipeline beyond ARV-110 and ARV-471. Data will be presented on our discovery of PROTAC protein degraders that recruit an E3 not previously reported for use with protein degrader technology. Topics discussed will include approaches for target and E3 selection, target and E3 ligand identification, and considerations for PROTAC design for human therapeutics.