Novel Insights into Structure–Activity Relationships of N‐Terminally Modified PACE4 Inhibitors. Issue 3 (11th January 2016)

• Record Type: Journal Article
• Authors: Kwiatkowska, Anna; Couture, Frédéric; Levesque, Christine; Ly, Kévin; Beauchemin, Sophie; Desjardins, Roxane; Neugebauer, Witold; Dory, Yves L.; Day, Robert
• Is Part Of: ChemMedChem. Volume 11:Issue 3(2016)
• Page Start: 289
• Page End: 301
• Publication Date: 2016-01-11
• Subjects: enzyme inhibitors -- PACE4 -- proprotein convertases -- prostate cancer -- structure–activity relationships; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201500532
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi‐Leu (ML) peptide, an octapeptide with the sequence Ac‐LLLLRVKR‐NH2 . Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N‐terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N‐terminal extension but by the protection of both ends with thed ‐Leu residue and 4‐amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile. Abstract : Keeping PACE with cancer : PACE4 is an emerging target in prostate cancer. With the aim to improve the properties of our lead inhibitor (Ac‐LLLLRVKR‐NH2 ) for in vivo administration, we designed N‐terminally modified analogues. PEGylation led to a loss of antiproliferative activity, whereas lipidation preserved or improved it. However, lipidated inhibitors showed increased toxicity; therefore the best analogue identified was obtained by the protection of either end withd ‐Leu and 4‐amidinobenzylamide.