Zoptarelin doxorubicin

Zoptarelin doxorubicin (developmental code names AEZS-108, AN-152) consists of doxorubicin linked to a small peptide agonist to the luteinizing hormone-releasing hormone (LHRH) receptor.[1] 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.[2]

Zoptarelin doxorubicin
Clinical data
Other namesAEZS-108; AN-152
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
PubChem CID
ChemSpider
CompTox Dashboard (EPA)
ECHA InfoCard100.244.989
Chemical and physical data
FormulaC91H117N19O26
Molar mass1893.044 g·mol−1
3D model (JSmol)
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

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 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.[3] Zoptarelin doxorubicin was discontinued for all indications under development in May 2017.[4]

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

Clinical trials

Promising results have been reported from a phase II clinical trial for ovarian cancer[5] and endometrial cancer.[6] 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.[7]

A phase III trial for endometrial cancer was initiated in April 2013 and it the primary completion date is estimated to be December 2016.[8] 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.[9]

References
  1. Rékási Z, Szöke B, Nagy A, Groot K, Rékási ES, Schally AV (May 1993). "Effect of luteinizing hormone-releasing hormone analogs containing cytotoxic radicals on the function of rat pituitary cells: tests in a long term superfusion system". Endocrinology. 132 (5): 1991–2000. doi:10.1210/endo.132.5.8477650. PMID 8477650.
  2. Engel J, Emons G, Pinski J, Schally AV (June 2012). "AEZS-108 : a targeted cytotoxic analog of LHRH for the treatment of cancers positive for LHRH receptors". Expert Opinion on Investigational Drugs. 21 (6): 891–9. doi:10.1517/13543784.2012.685128. PMID 22577891. S2CID 37548203.
  3. "Aeterna Zentaris Reconfirms Commitment to LHRH-receptor Targeting Zoptrex™ During 2016 ASCO Annual Meeting Pivotal Phase III Trial for Endometrial Cancer Expected to be Completed in Q3 2016". Aeterna Zentaris. 6 June 2016. Archived from the original on 4 February 2017.
  4. "Zoptarelin doxorubicin". Adis Insight. Springer Nature Switzerland AG.
  5. Emons G, Gorchev G, Sehouli J, Wimberger P, Stähle A, Hanker L, et al. (June 2014). "Efficacy and safety of AEZS-108 (INN: zoptarelin doxorubicin acetate) an LHRH agonist linked to doxorubicin in women with platinum refractory or resistant ovarian cancer expressing LHRH receptors: a multicenter phase II trial of the ago-study group (AGO GYN 5)". Gynecologic Oncology. 133 (3): 427–32. doi:10.1016/j.ygyno.2014.03.576. PMID 24713545.
  6. Emons G, Gorchev G, Harter P, Wimberger P, Stähle A, Hanker L, et al. (February 2014). "Efficacy and safety of AEZS-108 (LHRH agonist linked to doxorubicin) in women with advanced or recurrent endometrial cancer expressing LHRH receptors: a multicenter phase 2 trial (AGO-GYN5)". International Journal of Gynecological Cancer. 24 (2): 260–5. doi:10.1097/IGC.0000000000000044. PMC 3921259. PMID 24418927.
  7. Liu SV, Tsao-Wei DD, Xiong S, Groshen S, Dorff TB, Quinn DI, et al. (December 2014). "Phase I, dose-escalation study of the targeted cytotoxic LHRH analog AEZS-108 in patients with castration- and taxane-resistant prostate cancer". Clinical Cancer Research. 20 (24): 6277–83. doi:10.1158/1078-0432.CCR-14-0489. PMID 25278449.
  8. Clinical trial number NCT01767155 for "Zoptarelin Doxorubicin (AEZS 108) as Second Line Therapy for Endometrial Cancer (ZoptEC)" at ClinicalTrials.gov
  9. "Zoptarelin doxorubicin fails to extend survival in advanced endometrial cancer". Healio.com. 2 May 2017.
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