Abstract 731: 4-Amino-substituted 5-resorcinol-isoxazole derivatives, a novel class of Hsp90 inhibitor: Synthesis and evaluation of in vitro activity

Abstract

Abstract Hsp90 (heat shock protein 90) is a component of a molecular chaperone complex, involved in the folding, maturation and stabilisation of key signalling molecules which control cell proliferation, survival and transformation. It works by a modulation of a set of cancer-associated proteins, collectively referred to as “clients”. Inhibition of Hsp90 causes simultaneous destabilization and eventual degradation of client proteins that result in suppression of tumor growth. This observation led to the idea, among pharmaceutical chemists, to consider Hsp90 as a potential target for a new strategy in human cancer therapy. After pioneering studies with natural products (geldamycin and radicicol), many selective Hsp90 inhibitors from various institutions have entered in clinical trials. One of these classes of inhibitors is the 4,5-diaryl-isoxazole with a resorcinol in position 5 and a second substituted aryl in position 4. This scaffold was considered a prerequisite for the activity on Hsp90. VER-52296/NVP-AUY922, currently in Phase II clinical trials, belongs to diaryl-isoxazole class. In our project, we systematically investigated - with in silico pre-screening, in concert with structural information from X-ray protein crystallography - all possible modifications to make on the isoxazole scaffold. We have mainly focused our attention on the importance of an amide portion at the 4 position. Now we have identified a new class of synthetic small molecule Hsp90 inhibitors, characterized by a 4-amino-substituted 5-monoaryl-isoxazole (5-resorcinol-isoxazole) scaffold. We turned our attention to the 4 position of isoxazole where unexpectedly, we have found that compounds possessing a nitrogen atom directly attached to the isoxazole ring are endowed of activity against Hsp90 similar or even better than the diaryl analogues. Here we describe design, synthesis and preliminary in vitro biological profile of a small library of these derivatives. Examples from this series of compounds have activities ranging from low to high nM against Hsp90 as measured in a fluorescence polarization (FP) competitive binding assay, and are active in human cancer cell lines where they inhibit cell proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 731.