4,5-diarylisoxazole Hsp90 chaperone inhibitors: potential therapeutic agents for the treatment of cancer.
ABSTRACT Inhibitors of the Hsp90 molecular chaperone are showing considerable promise as potential chemotherapeutic agents for cancer. Here, we describe the structure-based design, synthesis, structure-activity relationships and pharmacokinetics of potent small-molecule inhibitors of Hsp90 based on the 4,5-diarylisoxazole scaffold. Analogues from this series have high affinity for Hsp90, as measured in a fluorescence polarization (FP) competitive binding assay, and are active in cancer cell lines where they inhibit proliferation and exhibit a characteristic profile of depletion of oncogenic proteins and concomitant elevation of Hsp72. Compound 40f (VER-52296/NVP-AUY922) is potent in the Hsp90 FP binding assay (IC50 = 21 nM) and inhibits proliferation of various human cancer cell lines in vitro, with GI50 averaging 9 nM. Compound 40f is retained in tumors in vivo when administered i.p., as evaluated by cassette dosing in tumor-bearing mice. In a human colon cancer xenograft model, 40f inhibits tumor growth by approximately 50%.
Article: Discovery of (2,4-dihydroxy-5-isopropylphenyl)-[5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl]methanone (AT13387), a novel inhibitor of the molecular chaperone Hsp90 by fragment based drug design.[show abstract] [hide abstract]
ABSTRACT: Inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) are currently generating significant interest in clinical development as potential treatments for cancer. In a preceding publication (DOI: 10.1021/jm100059d ) we describe Astex's approach to screening fragments against Hsp90 and the subsequent optimization of two hits into leads with inhibitory activities in the low nanomolar range. This paper describes the structure guided optimization of the 2,4-dihydroxybenzamide lead molecule 1 and details some of the drug discovery strategies employed in the identification of AT13387 (35), which has progressed through preclinical development and is currently being tested in man.Journal of Medicinal Chemistry 08/2010; 53(16):5956-69. · 4.80 Impact Factor
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ABSTRACT: Heat shock protein (Hsp90α) has been recently implicated in cancer prompting several attempts to discover and optimize new Hsp90α inhibitors. Toward this end, we explored the pharmacophoric space of 83 Hsp90α inhibitors using six diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure activity relationship (QSAR) of optimal predictive potential (r(67)(2)=0.811, F 42.8, r(LOO)(2)=0.748, r(PRESS)(2) (against 16 external test inhibitors) = 0.619). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the Hsp90α binding pocket. Receiver operating characteristic (ROC) curves analysis established the validity of QSAR-selected pharmacophores. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds and our in-house-built drugs and agrochemicals database (DAC). Twenty-five nanomolar and low micromolar Hsp90α inhibitors were identified. The most potent were formoterol, amodaquine, primaquine, and midodrine with IC(50) values of 3, 5, 6, and 20 nM, respectively.Journal of Chemical Information and Modeling 09/2010; 50(9):1706-23. · 4.68 Impact Factor
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ABSTRACT: The scaffold diversity of 7 representative commercial and proprietary compound libraries is explored for the first time using both Murcko frameworks and Scaffold Trees. We show that Level 1 of the Scaffold Tree is useful for the characterization of scaffold diversity in compound libraries and offers advantages over the use of Murcko frameworks. This analysis also demonstrates that the majority of compounds in the libraries we analyzed contain only a small number of well represented scaffolds and that a high percentage of singleton scaffolds represent the remaining compounds. We use Tree Maps to clearly visualize the scaffold space of representative compound libraries, for example, to display highly populated scaffolds and clusters of structurally similar scaffolds. This study further highlights the need for diversification of compound libraries used in hit discovery by focusing library enrichment on the synthesis of compounds with novel or underrepresented scaffolds.Journal of Chemical Information and Modeling 08/2011; 51(9):2174-85. · 4.68 Impact Factor