AEZS-108

Zoptarelin doxorubicin

Clinical data
ATC code	None
Legal status
Legal status	Investigational
Identifiers
IUPAC name [2-[(2S,4S)-4-[(2R,4S,5S,6S)-4-amino-5-hydroxy-6-methyl-tetrahydropyran-2-yl]oxy-2,5,12-trihydroxy-7-methoxy-6,11-dioxo-3,4-dihydro-1H-tetracen-2-yl]-2-oxo-ethyl] 5-[[(5R)-6-[[(1S)-1-[[(1S)-1-[(2S)-2-[(2-amino-2-oxo-ethyl)carbamoyl]pyrrolidine-1-carbonyl]-4-guanidino-butyl]carbamoyl]-3-methyl-butyl]amino]-5-[[(2S)-2-[[(2S)-3-hydroxy-2-[[(2S)-2-[[(2S)-3-(1H-imidazol-5-yl)-2-[[(2S)-5-oxopyrrolidine-2-carbonyl]amino]propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxo-hexyl]amino]-5-oxo-pentanoate
Synonyms	AN-152; AEZS-108
PubChem CID	16134409
ChemSpider	17290938
Chemical and physical data
Formula	C91H117N19O26
Molar mass	1,893.04 g·mol−1
3D model (Jmol)	Interactive image
SMILES CC1C(C(CC(O1)OC2CC(Cc3c2c(c4c(c3O)C(=O)c5cccc(c5C4=O)OC)O)(C(=O)COC(=O)CCCC(=O)NCCCCC(C(=O)NC(CC(C)C)C(=O)NC(CCCNC(=N)N)C(=O)N6CCCC6C(=O)NCC(=O)N)NC(=O)C(Cc7ccc(cc7)O)NC(=O)C(CO)NC(=O)C(Cc8c[nH]c9c8cccc9)NC(=O)C(Cc1cnc[nH]1)NC(=O)C1CCC(=O)N1)O)N)O
InChI InChI=1S/C91H117N19O26/c1-44(2)31-58(83(125)104-57(17-11-29-98-90(94)95)89(131)110-30-12-18-63(110)88(130)100-40-67(93)114)105-81(123)55(16-7-8-28-97-68(115)20-10-21-70(117)134-42-66(113)91(132)36-52-73(65(37-91)136-71-35-53(92)76(118)45(3)135-71)80(122)75-74(78(52)120)77(119)51-14-9-19-64(133-4)72(51)79(75)121)103-84(126)59(32-46-22-24-49(112)25-23-46)106-87(129)62(41-111)109-85(127)60(33-47-38-99-54-15-6-5-13-50(47)54)107-86(128)61(34-48-39-96-43-101-48)108-82(124)56-26-27-69(116)102-56/h5-6,9,13-15,19,22-25,38-39,43-45,53,55-63,65,71,76,99,111-112,118,120,122,132H,7-8,10-12,16-18,20-21,26-37,40-42,92H2,1-4H3,(H2,93,114)(H,96,101)(H,97,115)(H,100,130)(H,102,116)(H,103,126)(H,104,125)(H,105,123)(H,106,129)(H,107,128)(H,108,124)(H,109,127)(H4,94,95,98)/t45-,53-,55+,56-,57-,58-,59-,60-,61-,62-,63-,65-,71-,76+,91-/m0/s1 Key:OOUACICUAVTCEC-LZHWUUGESA-N

Zoptarelin doxorubicin consists of doxorubicin linked to a small peptide agonist to the luteinizing hormone-releasing hormone (LHRH) receptor. It has been developed as a potential treatment for a number of human cancers. The LHRH receptor is aberrantly present on the cell surface of approximately 80% of endometrial and ovarian cancers, 86% of prostate cancers and about 50% of breast cancers. Whereas in normal tissues, expression of this receptor is mainly confined to the pituitary gland, reproductive organs and hematopoietic stem cells. To a lesser extent the LHRH receptor is also found on the surface of bladder, colorectal, and pancreatic cancers, sarcomas, lymphomas, melanomas, and renal cell carcinomas.

The proposed method of action is that upon administration zoptarelin doxorubicin binds to the LHRH receptor and is subsequently internalized, concentrating the toxic doxorubicin within cancer cells and the small subset of normal tissues, as opposed to the completely systemic distribution observed with untargeted chemotherapeutics. The specific targeting of the doxorubicin to LHRH receptor bearing cells is also proposed to reduce the cardiotoxicity observed in the administration of unconjugated doxorubicin.

Zoptarelin doxorubicin is also known as AEZS-108 (previously AN-152).

Zoptarelin doxorubicin was invented by Andrew V. Schally while at the Tulane University School of Medicine, New Orleans and subsequently at the Sylvester Comprehensive Cancer Center, University of Miami. It has been subsequently developed by AEterna Zentaris Inc. In June 2016, Aeterna stated that it plans to submit an NDA to the FDA by mid 2017.

The U.S. Food and Drug Administration (FDA) has granted it orphan drug status for ovarian cancer and endometrial cancer.

Promising results have been reported from a phase II clinical trial for ovarian cancer and endometrial cancer. Phase II trials have also been undertaken for prostate, breast and bladder cancer, although no results for these trials have been reported in peer-reviewed literature. A phase I trial in prostate cancer indicated that nine out ten evaluable patients achieved disease stabilization through administration of zoptarelin doxorubicin.

A phase III trial for endometrial cancer was initiated in April 2013 and it the primary completion date is estimated to be December 2016. In May 2017 the results were disclosed, showing that the drug did not extend overall survival nor did it improve the safety profile compared to doxorubicin.