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 (mCRPC).^[1][2] It belongs to a class of drugs called proteolysis targeting chimeras (PROTACs), which are designed to selectively degrade specific proteins by hijacking the ubiquitin-proteasome system.^[3] 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.^[3] 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.^[3] As of 2024, luxdegalutamide is being evaluated in phase I/II clinical trials for prostate cancer.^[1][2][4]

Luxdegalutamide

Clinical data
Other names	ARV-766,JSB462
Routes of administration	Oral
Legal status
Legal status	Investigational
Identifiers
IUPAC name (83S)-N-[(1r,3S)-3-(4-cyano-3-methoxyphenoxy)-2,2,4,4-tetramethylcyclobutyl]-53-fluoro-6,82,86-trioxo-7-aza-4(1,4)-piperazina-2(1,4),8(3)-dipiperidina- 1(1),5(1,4)-dibenzenaoctaphane-14-carboxamide
CAS Number	2750830-09-0
PubChem CID	156504141
ChemSpider	128921978
UNII	5BD7R933PV
KEGG	D13059
ChEMBL	ChEMBL5314528
Chemical and physical data
Formula	C45H54FN7O6
Molar mass	807.968 g·mol−1
3D model (JSmol)	Interactive image
SMILES CC1(C(C(C1OC2=CC(=C(C=C2)C#N)OC)(C)C)NC(=O)C3=CC=C(C=C3)N4CCC(CC4)CN5CCN(CC5)C6=CC(=C(C=C6)C(=O)N[C@H]7CCC(=O)NC7=O)F)C
InChI InChI=InChI=1S/C45H54FN7O6/c1-44(2)42(45(3,4)43(44)59-33-12-8-30(26-47)37(25-33)58-5)50-39(55)29-6-9-31(10-7-29)52-18-16-28(17-19-52)27-51-20-22-53(23-21-51)32-11-13-34(35(46)24-32)40(56)48-36-14-15-38(54)49-41(36)57/h6-13,24-25,28,36,42-43H,14-23,27H2,1-5H3,(H,48,56)(H,50,55)(H,49,54,57)/t36-,42?,43?/m0/s1 Key:RDPPBRKNBBXPNZ-PJXMSJPKSA-N

Mechanism of action

Luxdegalutamide is a heterobifunctional PROTAC that targets the androgen receptor for degradation.^[5] 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.^[6]

Luxdegalutamide has demonstrated the ability to degrade both wild-type androgen receptor and clinically relevant AR ligand-binding domain (LBD) mutants, including the most prevalent AR L702H, H875Y, and T878A mutations that commonly arise in treatment-resistant prostate cancer.^[7]

Development history

Luxdegalutamide was initially developed by Celgene and later acquired by Bristol Myers Squibb.^[8] The drug entered phase I clinical trials on June 22, 2020, with the primary objective of evaluating safety, tolerability, pharmacokinetics, and pharmacodynamics in patients with metastatic castration-resistant prostate cancer.^[8] Arvinas later gained rights to develop the compound and has since partnered with Novartis for global development and commercialization.^[9]

Current clinical trials

As of 2025, luxdegalutamide is being evaluated in multiple phase II clinical trials for prostate cancer. A major ongoing study aims to evaluate the efficacy and safety of luxdegalutamide (JSB462) at 100 mg and 300 mg once-daily doses in combination with abiraterone compared with standard androgen receptor pathway inhibitors (abiraterone or enzalutamide) in participants with metastatic hormone-sensitive prostate cancer (mHSPC).^[10] The study is designed to select the recommended dose of the combination for potential phase III development.^[11][12][13]

Regulatory status

Luxdegalutamide currently holds investigational status and has not received regulatory approval for commercial use in any jurisdiction.^[14] The drug is being studied under Investigational New Drug applications in clinical trials conducted by Arvinas and its development partners.^[15]