Luxdegalutamide
Luxdegalutamide, also known as ARV-766 and JSB462, is an investigational oral androgen receptor (AR) degrader being developed by Arvinas for the treatment of metastatic castration-resistant prostate cancer. It belongs to a class of drugs called proteolysis targeting chimeras, which are designed to selectively degrade specific proteins by hijacking the ubiquitin-proteasome system. Luxdegalutamide is a second-generation PROTAC AR degrader that has demonstrated a broader efficacy profile and better tolerability compared to its predecessor, ARV-110, in clinical settings. It has shown promise in overcoming resistance associated with certain AR mutations, including the L702H mutation, which is prevalent in up to 24% of treated mCRPC patients. As of 2024, luxdegalutamide is being evaluated in phase I/II clinical trials for prostate cancer.
Mechanism of action
Luxdegalutamide is a heterobifunctional PROTAC that targets the androgen receptor for degradation. Unlike conventional androgen receptor antagonists that merely block the receptor's activity, PROTACs like luxdegalutamide recruit the cellular protein degradation machinery to completely eliminate the target protein from the cell. The drug works by forming a ternary complex between the androgen receptor, the PROTAC molecule itself, and an E3 ubiquitin ligase, which then tags the receptor protein for degradation by the proteasome.Luxdegalutamide has demonstrated the ability to degrade both wild-type androgen receptor and clinically relevant AR ligand-binding domain mutants, including the most prevalent AR L702H, H875Y, and T878A mutations that commonly arise in treatment-resistant prostate cancer.