Article

Purine-scaffold Hsp90 inhibitors

Department of Medicine and Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
IDrugs: the investigational drugs journal (Impact Factor: 2.33). 12/2006; 9(11):778-82.
Source: PubMed

ABSTRACT Heat shock protein 90 (Hsp90) has emerged as an important target, the inhibition of which is aimed at a wide range of cell transformations that lead to malignancy. A clinical evaluation of 17-AAG, the first Hsp90 inhibitor to enter the clinic, revealed evidence of activity for the compound at a manageable level of toxicity. However, clinical results have also demonstrated the limitations of this drug. The identification of novel Hsp90 inhibitor classes with improved structural characteristics and better pharmacological profiles has therefore become a major focus of interest in the field of cancer therapeutics. This feature describes the purine-scaffold class of Hsp90 inhibitors, focusing on research efforts from the discovery stage to the clinical translation of such compounds.

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    • "Hsp90 negatively regulates Hsp70 expression by blocking activation of the transcription factor HSF-1; thus inhibitors result in Hsp70 induction [15]. Geldanamycin is a naturally occurring benzoquinone that blocks Hsp90 interaction with HSF-1 resulting in enhanced Hsp70 expression [16]. However, its utility is limited by hepatotoxicity and poor brain permeability. "
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    PLoS ONE 01/2014; 9(1):e86048. DOI:10.1371/journal.pone.0086048 · 3.23 Impact Factor
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    • "However, structurally related compounds to GA, including 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), were found to be suboptimal and Therapeutic Advances in Neurological Disorders 7 (1) 44 http://tan.sagepub.com human clinical trials in the cancer field presented with varying problems including drug-induced liver injury [Waza et al. 2006] (discussed elsewhere [Chiosis and Tao, 2006]). In light of this, a group of chemically dissimilar Hsp90-inhibiting compounds was screened; the compounds belong to the SNX-2112 drug class which was found to be a promising alternative in the cancer field [Chandarlapaty et al. 2008; Okawa et al. 2009]. "
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    Therapeutic Advances in Neurological Disorders 01/2014; 7(1):33-51. DOI:10.1177/1756285613493469
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    • "HSP-90 inhibitors, such as 17-AAG and radicicol, have similar neuroprotective effects as those of HSF-1 and HSP-70 up-regulation [58,59]. The blood-brain barrier permeability presents a limitation [60,61]. 17-AAG is currently in phase II trials as an antitumor compound [62,63], showing neuroprotective effects in preclinical models of Huntington's disease and spinocerebellar ataxias [57,59]. "
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