Discovery of PI-1840, a novel noncovalent and rapidly reversible proteasome inhibitor with anti-tumor activity

Abstract

Background: Food and Drug Administration-approved proteasome inhibitors act covalently, which hampers their safety. Results: Structure activity relationship (SAR) studies, mass spectrometry, and dialysis identified PI-1840 as a noncovalent proteasome inhibitor that sensitizes human cancer cells to p53 and Bcl2 antagonists. Conclusion: Noncovalent proteasome inhibitors suppress in vivo tumor growth with little toxicity in mouse xenografts. Significance: Discovery of noncovalent proteasome inhibitors warrants their development as anti-cancer drugs. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.