Novel Insights into Structure-Activity Relationships of N-Terminally Modified PACE4 Inhibitors.

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 the D-Leu residue and 4-amindinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile.

ChemMedChem. 2016 Jan 11 [Epub ahead of print]

Anna Kwiatkowska, Frédéric Couture, Christine Levesque, Kévin Ly, Sophie Beauchemin, Roxane Desjardins, Witold Neugebauer, Yves L Dory, Robert Day

Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). , Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). , Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). , Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). , Département de chimie, Faculté des Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord, Sherbrooke, Québec J1H 5N4 (Canada). , Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). , Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). , Département de chimie, Faculté des Sciences, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord, Sherbrooke, Québec J1H 5N4 (Canada). Yves. Dory@USherbrooke. ca. , Département de Chirurgie/Urologie, Faculté de Médecine et Sciences de la Santé, Institut de pharmacologie de Sherbrooke, Université de Sherbrooke, 3001, 12e Ave. Nord Sherbrooke, Sherbrooke, Québec, J1H 5N4 (Canada). 

PubMed