Gridegalutamide

Gridegalutamide is an investigational oral androgen receptor (AR) degrader being developed for the treatment of metastatic castration-resistant prostate cancer (mCRPC). 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.^[1][2] CC-94676 employs a unique dual mechanism of action, combining AR degradation with AR antagonism, potentially offering advantages over traditional AR inhibitors in overcoming resistance mechanisms.^[3] Initially developed by Celgene and now under Bristol Myers Squibb, CC-94676 has demonstrated AR protein degradation and suppression of tumor growth in CRPC mouse models.^[2] As of 2024, CC-94676 is being evaluated in phase I clinical trials for patients with mCRPC who have progressed on androgen-deprivation therapy and at least one prior secondary hormonal therapy.^[1][2]

Gridegalutamide

Clinical data
Other names	BMS-986365; CC-94676
Identifiers
IUPAC name 2-[(2R)-4-[2-[4-[3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl]-2-ethylphenoxy]ethyl]-2-methylpiperazin-1-yl]-N-[3-[[(3R)-2,6-dioxopiperidin-3-yl]amino]phenyl]acetamide
CAS Number	2446929-86-6
PubChem CID	153513643
UNII	VA228VR2DI
KEGG	D12866
Chemical and physical data
Formula	C41H45F3N8O5S
Molar mass	818.92 g·mol−1
3D model (JSmol)	Interactive image
SMILES CCC1=C(C=CC(=C1)N2C(=S)N(C(=O)C2(C)C)C3=CC(=C(C=C3)C#N)C(F)(F)F)OCCN4CCN([C@@H](C4)C)CC(=O)NC5=CC=CC(=C5)N[C@@H]6CCC(=O)NC6=O
InChI InChI=InChI=1S/C41H45F3N8O5S/c1-5-26-19-31(52-39(58)51(38(56)40(52,3)4)30-10-9-27(22-45)32(21-30)41(42,43)44)11-13-34(26)57-18-17-49-15-16-50(25(2)23-49)24-36(54)47-29-8-6-7-28(20-29)46-33-12-14-35(53)48-37(33)55/h6-11,13,19-21,25,33,46H,5,12,14-18,23-24H2,1-4H3,(H,47,54)(H,48,53,55)/t25-,33-/m1/s1 Key:YUVGVJYLOFTILT-INJOXJOKSA-N

References

1. Salama AK, Trkulja MV, Casanova E, Uras IZ (December 2022). "Targeted Protein Degradation: Clinical Advances in the Field of Oncology". International Journal of Molecular Sciences. 23 (23): 15440. doi:10.3390/ijms232315440. PMC 9741350. PMID 36499765.
2. Xie H, Liu J, Alem Glison DM, Fleming JB (2021). "The clinical advances of proteolysis targeting chimeras in oncology". Exploration of Targeted Anti-tumor Therapy. 2 (6): 511–521. doi:10.37349/etat.2021.00061. PMC 9400722. PMID 36046114.
3. Rathkopf DE, Patel MR, Choudhury AD, Rasco D, Lakhani N, Hawley JE, et al. (September 2024). "Safety and clinical activity of BMS-986365 (CC-94676), a dual androgen receptor ligand-directed degrader and antagonist, in heavily pretreated patients with metastatic castration-resistant prostate cancer". Annals of Oncology. doi:10.1016/j.annonc.2024.09.005. PMID 39293515.