Early Development of a KISS1/GPR54 Receptor Agonist for Prostate Cancer
Yvonne Angella, Yan Wanga, Yun Wub, Wen Jieb, Chen Haixia b, Yanfen Tengb,
Meng Xiangminb, Krishna Kodukulac, and Robert Drakasc
aDepartment of Peptide Chemistry, ChemPartner SSF
bDepartment of Peptide Chemistry, ChemPartner Shanghai
cShangPharma Innovation, 280 Utah Avenue, Suite 250, SSF, CA 94080
Metastin/kisspeptin is a C-terminal amidated peptide of 54 amino acid residues in length isolated from human placental tissue. It is a ligand of the orphan G-protein-coupled receptor KISS1R, also called GPR54, which is expressed throughout the central nervous system and in a variety of endocrine and gonadal tissues. Kisspeptin plays a pivotal role in controlling gonadotropin-releasing hormone (GnRH) neurons. Kisspeptin acts directly on the GnRH neurons to stimulate GnRH release.1 Compared to the full-length metastin protein, the N-terminally truncated peptide metastin(45–54) has 3–10 times higher receptor affinity and enhanced ability to increase intracellular calcium concentration, which is essential for activation of protein kinases involved in intracellular signaling in a number of pathways that affect reproduction and cell migration.2 KISS1R receptor agonists and antagonists have been explored to investigate the biology of targeting the KISS1 receptor. Metastin(45–54) analogues with higher agonist activity and improved metabolic stability have been reported in the literature, and shown to suppress plasma testosterone in male rats with continuous subcutaneous administration.3 Several KISS1R agonists have reached phase II in the clinic.4
Continuous subcutaneous administration of KISS1R agonists has been shown to induce a transient increase in plasma testosterone, followed by abrupt reduction of plasma testosterone to castrate levels within 3–7 days, which can be sustained throughout a 4-week dosing period. These suppressive effects are more rapid and profound than those induced by the GnRH agonist analog leuprolide.3 Hormonal therapy involving luteinizing hormone (LH)-releasing hormone agonists (LHRHs) is a widely used systemic treatment for prostate cancer and is recommended in the European Association of Urology guidelines on prostate cancer for use in patients with locally advanced and metastatic disease.5 We sought to design novel peptides with increased activity against KISS1R along with significantly enhanced plasma stability over previously reported KISS1R agonist compounds, and demonstrate in vivo efficacy of these novel peptides. The peptides were rationally designed based on Ala scanning and known SAR, and screened in vitro in a GPR54-NFAT-bla CHO-K1 cell-based primary assay, as well as a cell migration secondary assay used to test the peptides’ effect on migratory properties of cells stably expressing human KISS1R. Lead peptides selected from the in vitro results were screened for plasma stability and in vivo efficacy. The lead peptide, YA-156, demonstrated potent in vitro as well as in vivo efficacy in a subcutaneous, xenograft x1LnCAP BALB/c nude mouse prostate cancer model, excellent plasma stability, and a good in vitro ADME profile, aside from some unexpected receptor selectivity results.
Further studies are currently in progress to assess the in vivo effects of these novel KISS1R analogs. Chronic administration of kisspeptin analogs via a sustained release formulation may hold promise of a novel therapeutic approach for suppressing reproductive functions and hormone-related diseases, such as prostate cancer.
1. Kotani, M. et al., J. Biol. Chem., 2001, 276(37), 34631–34636.
2. Ohtaki, T. et al., Nature, 2001, 411, 613.
3. Matsui, H. et al., Eur. J. Pharmacol., 2014, 735, 77–85.
4. MacLean, D.B. et al., J. Clin. Endocrinol Metab., 2014, 99(8), E1445–E1453.
5. EAU Guidelines on prostate cancer, 2007, www.uroweb.org.