Abstract 1810: PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity

Non-covalent proteasome inhibitors that are less toxic and more effective against solid tumors than currently used proteasome inhibitors are desirable. Through HTS and hit-to-lead optimization efforts we have identified PI-1840, a potent and selective inhibitor for chymotrypsin-like (CT-L) (IC 50 value = 27 ± 0.14 nM) over T-L and PGPH (IC 50 values >100 µM) activities of the proteasome. Furthermore, PI-1840 is over 100-fold more selective for the constitutive proteasome over the immunoproteasome. Dialysis and mass spectrometry studies demonstrate that PI-1840 is a non-covalent and rapidly reversible CT-L inhibitor. PI-1840 inhibits CT-L activity, induces the accumulation of proteasome substrates p27, Bax and IκB-α, inhibits survival pathways and proliferation, and induces apoptosis in human cancer cells. The mdm2/p53 disruptor, nutlin, sensitizes cancer cells to PI-1840 in a p53-dependent manner. Furthermore, the pan Bcl-2 antagonist BH3-M6 also sensitizes cancer cells to PI-1840. Finally, in vivo, PI-1840 but not Bortezomib (clinically used proteasome inhibitor) suppresses the growth in nude mice of human breast xenografts. These results warrant further evaluation of non-covalent and rapidly reversible proteasome inhibitor as potential anticancer agents against solid tumors. Citation Format: Said M. Sebti, Aslamuzzaman Kazi, Sevil Ozcan, Awet G. Tecleab, Ying Sun, Harshani Lawrence. PI-1840, a novel non-covalent and rapidly reversible proteasome inhibitor with anti-tumor activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1810. doi:10.1158/1538-7445.AM2014-1810