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Evaluation of 8-arylsulfanyl, 8-arylsulfoxyl, and 8-arylsulfonyl adenine derivatives as inhibitors of the heat shock protein 90

Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Journal of Medicinal Chemistry (Impact Factor: 5.48). 05/2005; 48(8):2892-905. DOI: 10.1021/jm049012b
Source: PubMed

ABSTRACT Hsp90 is a chaperone protein with important roles in maintaining transformation and in elevating the survival and growth potential of cancer cells. Currently there is an increasing interest in developing inhibitors of this protein as anticancer therapeutics. One of such inhibitors, the purine-scaffold class, has been reported to be potent and selective against Hsp90 both in vitro and in vivo models of cancer. Here, a series of 8-arylsulfanyl, -sulfoxyl, and -sulfonyl adenine members of the purine class was synthesized and evaluated as inhibitors of the chaperone. The structure-activity relationship and selectivity for tumor Hsp90 of compounds within the series is presented. Our results suggest that 8-arylsulfanyl adenine derivatives are good inhibitors of chaperone activity, whereas oxidation of the sulfides to sulfoxides or sulfones leads to compounds of decreased activity. The study identifies derivative 11v as the most potent Hsp90 inhibitor of the purine-scaffold series published to date (EC(50) = 30 nM), and also as the compound of this class with highest selectivity for tumor vs normal cell Hsp90 (700 to 3000-fold). Most rewardingly, this work has allowed for the identification of Hsp90 inhibitors with selective affinities for Hsp90-client protein complexes, derivatives that may represent useful pharmacological tools in dissecting Hsp90-regulated processes.

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    • "PU3 thus became a starting point for the expansion and the improvement of clinically applicable purine-scaffold Hsp90 inhibitors, where efforts are directed toward either position C8 or C9 of purine (Chiosis, 2006). These synthetic derivatives could be roughly categorized to 8-benzyl (He et al., 2006;Vilenchik et al., 2004), 8- phenylsylfanyl (He et al., 2006;Llauger et al., 2005), 8-(7′-substituted benzothiazolothio) (Zhang et al., 2006), and 9-benzyl purine derivatives (Kasibhatla et al., 2007). Major improvements of purine-scaffold Hsp90 inhibitors include insensitivity to multi-drug resistance (Rodina et al., 2007), favorable water solubility, oral bioavailability, and metabolic stability (Biamonte et al., 2006;He et al., 2006;Kasibhatla et al., 2007;Zhang et al., 2006). "
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    ABSTRACT: The molecular chaperone Hsp90 (heat shock protein 90) is a promising target in cancer therapy. Preclinical and clinical evaluations of a variety of Hsp90 inhibitors have shown anti-tumor effect as a single agent and in combination with chemotherapy. Current Hsp90 inhibitors are categorized into several classes based on distinct modes of inhibition, including (i) blockade of ATP binding, (ii) disruption of co-chaperone/Hsp90 interactions, (iii) antagonism of client/Hsp90 associations and (iv) interference with post-translational modifications of Hsp90. The different functions of Hsp90 isoforms and the isoform selectivity of drugs need further investigation. The correlation of cell surface Hsp90 with cancer metastasis and the emerging involvement of Hsp90 inhibition in cancer stem cells have become exciting areas that could be exploited. Therefore, the aim of this review is (1) to summarize the up-to-date knowledge of mechanistic studies and clinical prospect of currently available Hsp90 inhibitors, (2) to enhance our perspectives for designing and discovering novel Hsp90 inhibitors, and (3) to provide an insight into less-understood potential of Hsp90 inhibition in cancer therapy.
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    • "Nucleotide exchange and ATP hydrolysis (by Hsp90 itself, with the assistance of co-chaperones) drive the so-called Hsp90 chaperone machine to bind, chaperone, and release client proteins. Indeed, identifi cation of the GA binding site as a nucleotide pocket favoring purines led Chiosis and colleagues to design a series of highly potent purine scaffold Hsp90 inhibitors with markedly improved drug-like properties (Chiosis et al 2002; Chiosis et al 2003; Llauger et al 2005; He et al 2006). Workman and colleagues used a high-throughput screen based on inhibition of Hsp90 ATPase activity to identify 3,4- diarylpyrazoles as a novel class of Hsp90 inhibitors (Cheung et al 2005; Dymock et al 2005). "
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    ABSTRACT: Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signaling proteins, as well as multiple mutated, chimeric, and/or over-expressed signaling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple cellular signaling pathways. By inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90 inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client proteins are neurotoxic, these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90 inhibitors in treating multiple pathologies involving neurodegeneration
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    • "Nucleotide exchange and ATP hydrolysis (by Hsp90 itself, with the assistance of co-chaperones) drive the so-called Hsp90 chaperone machine to bind, chaperone, and release client proteins. Indeed, identifi cation of the GA binding site as a nucleotide pocket favoring purines led Chiosis and colleagues to design a series of highly potent purine scaffold Hsp90 inhibitors with markedly improved drug-like properties (Chiosis et al 2002; Chiosis et al 2003; Llauger et al 2005; He et al 2006). Workman and colleagues used a high-throughput screen based on inhibition of Hsp90 ATPase activity to identify 3,4- diarylpyrazoles as a novel class of Hsp90 inhibitors (Cheung et al 2005; Dymock et al 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Heat shock protein 90 (Hsp90) is a molecular chaperone required for the stability and function of a number of conditionally activated and/or expressed signalling proteins, as well as multiple mutated, chimeric, and/or over-expressed signalling proteins, that promote cancer cell growth and/or survival. Hsp90 inhibitors are unique in that, although they are directed towards a specific molecular target, they simultaneously inhibit multiple cellular signalling pathways. By inhibiting nodal points in multiple overlapping survival pathways utilized by cancer cells, combination of an Hsp90 inhibitor with standard chemotherapeutic agents may dramatically increase the in vivo efficacy of the standard agent. Hsp90 inhibitors may circumvent the characteristic genetic plasticity that has allowed cancer cells to eventually evade the toxic effects of most molecularly targeted agents. The mechanism-based use of Hsp90 inhibitors, both alone and in combination with other drugs, should be effective toward multiple forms of cancer. Further, because Hsp90 inhibitors also induce Hsf-1-dependent expression of Hsp70, and because certain mutated Hsp90 client proteins are neurotoxic, these drugs display ameliorative properties in several neurodegenerative disease models, suggesting a novel role for Hsp90 inhibitors in treating multiple pathologies involving neurodegeneration.
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