molecules of the year

The Arvinas ER chimeric degrader, ARV-471, is an oral, bioavailable ER degrading CRBN-based  PROTAC for the treatment of patients with ER+/HER2- breast cancer. Along with ARV-110, it is one of the first chimeric degraders to enter a Ph. II clinical trial. It was first disclosed at AACR in early 2021, and though the molecules have not been formally published yet, related analogs have been published and characterized. ER degradation with SERDs like fulvestrant is a well-validated mechanism, but fulvestrant doesn’t appear to achieve complete degradation of ER. ARV-471 achieves deeper tumor regression in preclinical models over fulvestrant, at much lower doses, and has a more prominent effect in combination with CDK4/6 inhibitor palbociclib. In humans, the molecule has an effective…