Abstract 1359: Identification of a novel class of compounds as proteasome inhibitors: Synthesis and structure activity relationship studies of PI-1833 library

Abstract

Listen

Translate article

Abstract The ATP-dependent ubiquitin-proteosome pathway is responsible for the controlled degradation of proteins in eukaryotic cells. The 26S proteosome is a multifunctional complex, consisting of a 19S regulatory particle (RP) and a 20S core particle (CP). The three main catalytic activities of the proteasome; peptidylglutamyl peptide hydrolysing (PGPH), trypsin-like (T-L), and chymotrypsin-like (CT-L), are mediated by three distinct catalytic β-1, β-2, and β-5 subunits, respectively. Owing to the central role of proteosome in maintaining homeostasis and hence its key position in many cellular processes, the development of inhibitors for CT-L activity has been the subject of considerable interest in the treatment of cancer. Selective inhibition of the CT-L activity of 20S proteasome represents a successful strategy in cancer therapy as demonstrated by Bortezomib (Velcade), a clinically approved drug for multiple myeloma and mantle lymphoma. Toxicity and tumor cell resistance against Bortezomib demand the development of improved and selective proteasome inhibitors. The potent proteasome inhibitors reported to date have been developed as aldehydes, boronates, vinylsulfones and expoxyketones and these compounds function through covalent modification of the N-terminal threonine residue of β-5 subunit. Small, drug-like synthetic proteasome inhibitors that are selective for cancer over normal cells are rare, but clearly would have a potential advantage over the existing inhibitors. PI-1833 was identified in our program as a ‘hit’ with in-vitro CT-L proteasome activity (IC50 = 0.58 μM). PI-1833 is a small molecule with oxadiazole pharmacophore and presents 3 points of diversity amenable for focused library synthesis. Lack of a reactive chemical moiety (or electrophilic moiety) to form proteasome adducts is an important feature of PI-1833. The first generation analogs of PI-1833 have shown promising SAR (in-vitro and in-vivo) toward proteasome inhibition with the IC50 values ranging from 0.3-0.7 μM. In this work we will present in-vitro and in-vivo structure activity relationship (SAR) data, synthesis and selectivity of a PI-1833 library and discuss the mode of proteasome inhibition (co-valent vs non co-valent) by this class of compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1359. doi:10.1158/1538-7445.AM2011-1359