Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor

Journal of Medicinal Chemistry
Anna KwiatkowskaRobert Day

Abstract

PACE4 plays an important role in the progression of prostate cancer and is an attractive target for the development of novel inhibitor-based tumor therapies. We previously reported the design and synthesis of a novel, potent, and relatively selective PACE4 inhibitor known as a Multi-Leu (ML) peptide. In the present work, we examined the ML peptide through detailed structure-activity relationship studies. A variety of ML-peptide analogues modified at the P8-P5 positions with leucine isomers (Nle, DLeu, and DNle) or substituted at the P1 position with arginine mimetics were tested for their inhibitory activity, specificity, stability, and antiproliferative effect. By incorporating d isomers at the P8 position or a decarboxylated arginine mimetic, we obtained analogues with an improved stability profile and excellent antiproliferative properties. The DLeu or DNle residue also has improved specificity toward PACE4, whereas specificity was reduced for a peptide modified with the arginine mimetic, such as 4-amidinobenzylamide.

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Citations

Jan 8, 2015·Expert Opinion on Therapeutic Patents·Frédéric CoutureRobert Day
May 25, 2015·Biochemical Pharmacology·Bruno Ramos-MolinaIris Lindberg
Sep 16, 2014·Neoplasia : an International Journal for Oncology Research·Frédéric CoutureBrigitte Guérin
Mar 24, 2017·ChemMedChem·Kornelia HardesTorsten Steinmetzer
Oct 24, 2017·ChemMedChem·Teodora IvanovaTorsten Steinmetzer
May 15, 2015·ChemMedChem·Kornelia HardesTorsten Steinmetzer
Aug 28, 2014·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Indrajit MaityApurba K Das
Oct 11, 2017·Cancer Research·Frédéric CoutureRobert Day
Mar 20, 2021·ACS Medicinal Chemistry Letters·Monika A Lewandowska-GochRobert Day
Dec 7, 2018·Journal of Medicinal Chemistry·Vahid DianatiYves L Dory

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