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).
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.
Available from: Darius Ebrahimi-Fakhari
- "Hsp90 negatively regulates Hsp70 expression by blocking activation of the transcription factor HSF-1; thus inhibitors result in Hsp70 induction . Geldanamycin is a naturally occurring benzoquinone that blocks Hsp90 interaction with HSF-1 resulting in enhanced Hsp70 expression . However, its utility is limited by hepatotoxicity and poor brain permeability. "
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ABSTRACT: Hsp90 inhibitors such as geldanamycin potently induce Hsp70 and reduce cytotoxicity due to α-synuclein expression, although their use has been limited due to toxicity, brain permeability, and drug design. We recently described the effects of a novel class of potent, small molecule Hsp90 inhibitors in cells overexpressing α-synuclein. Screening yielded several candidate compounds that significantly reduced α-synuclein oligomer formation and cytotoxicity associated with Hsp70 induction. In this study we examined whether chronic treatment with candidate Hsp90 inhibitors could protect against α-synuclein toxicity in a rat model of parkinsonism. Rats were injected unilaterally in the substantia nigra with AAV8 expressing human α-synuclein and then treated with drug for approximately 8 weeks by oral gavage. Chronic treatment with SNX-0723 or the more potent, SNX-9114 failed to reduce dopaminergic toxicity in the substantia nigra compared to vehicle. However, SNX-9114 significantly increased striatal dopamine content suggesting a positive neuromodulatory effect on striatal terminals. Treatment was generally well tolerated, but higher dose SNX-0723 (6-10 mg/kg) resulted in systemic toxicity, weight loss, and early death. Although still limited by potential toxicity, Hsp90 inhibitors tested herein demonstrate oral efficacy and possible beneficial effects on dopamine production in a vertebrate model of parkinsonism that warrant further study.
Available from: Daryl Rhys Jones
- "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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ABSTRACT: Parkinson's disease is a slowly progressive neurodegenerative disorder typically characterized by the loss of dopaminergic neurons within the substantia nigra pars compacta, and the intraneuronal deposition of insoluble protein aggregates chiefly comprised of α-synuclein. Patients experience debilitating symptoms including bradykinesia, rigidity and postural instability. No curative treatment currently exists and therapeutic strategies are restricted to symptomatic treatment only. Over the past decade a class of molecular chaperones called the heat shock proteins has emerged as a potentially promising therapeutic target. Heat shock proteins aid in the folding and refolding of proteins, and target denatured proteins to degradation systems. By targeting heat shock proteins through various means including overexpression and pharmacological enhancement, researchers have shown that α-synuclein aggregation and its associated cytotoxicity can be therapeutically modulated in an array of cell and animal models. This review highlights the relevant progress in this field and discusses the relevance of heat shock proteins as therapeutic modulators of α-synuclein toxicity to the rapidly evolving understanding of Parkinson's disease pathogenesis.
Available from: Araceli Espinosa-Jeffrey
- "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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ABSTRACT: Periventricular leukomalacia (PVL) is the most frequent cause of cerebral palsy and other intellectual disabilities, and currently there is no treatment. In PVL, glutamate excitotoxicity (GME) leads to abnormal oligodendrocytes (OLs), myelin deficiency, and ventriculomegaly. We have previously identified that the combination of transferrin and insulin growth factors (TSC1) promotes endogenous OL regeneration and remyelination in the postnatal and adult rodent brain. Here, we produced a periventricular white matter lesion with a single intracerebral injection of N-methyl-d-aspartate (NMDA). Comparing lesions produced by NMDA alone and those produced by NMDA + TSC1 we found that: NMDA affected survival and reduced migration of OL progenitors (OLPs). In contrast, mice injected with NMDA + TSC1 proliferated twice as much indicating that TSC1 supported regeneration of the OLP population after the insult. Olig2-mRNA expression showed 52% OLP survival in mice receiving a NMDA injection and increased to 78% when TSC1 + NMDA were injected simultaneously and ventricular size was reduced by TSC1. Furthermore, in striatal slices TSC1 reduced the inward currents induced by NMDA in medium-sized spiny neurons, demonstrating neuroprotection. Thus, white matter loss after excitotoxicity can be partially rescued as TSC1 conferred neuroprotection to preexisting OLP and regeneration via OLP proliferation. Furthermore, we showed that early TSC1 administration maximizes neuroprotection.
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