Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer

Rodina, Anna; Vilenchik, Maria; Moulick, Kamalika; Aguirre, Julia; Kim, Joungnam; Chiang, Anne C.; Litz, Julie; Clement, Cristina C.; Kang, Yanlong; She, Yuhong; Wu, Nian; Felts, Sara J.; Wipf, Peter; Massagué, Joan; Jiang, Xuejun; Brodsky, Jeffrey L.; Krystal, Geoffrey W.; Chiosis, Gabriela

doi:10.1038/nchembio.2007.10

Cited by 148 publications

(125 citation statements)

References 38 publications

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“…The protection conferred by HSPs is not limited to these "chaperone" activities; HSPs also inhibit lipid peroxidation and oxidative damage to DNA (Park et al 1998;Su et al 1999;Martindale and Holbrook 2002). In addition, HSPs have been shown to inhibit multiple pro-apoptotic signaling events (Jaattela et al 1998;Beere et al 2000;Pandey et al 2000a, b;Concannon et al 2001Concannon et al , 2003Tsuchiya et al 2003;Stankiewicz et al 2005;Rodina et al 2007;Jiang et al 2009;Evans et al 2010;Pasupuleti et al 2010). HO-1 is a heat shock-inducible protein that lacks intrinsic chaperone activity; however, it inhibits oxidative stress, inflammation, and apoptosis in multiple tissue types (Kirkby and Adin 2006;Ryter et al 2006;Gozzelino et al 2010;Paine et al 2010;Blancou et al 2011).…”

Section: Discussionmentioning

confidence: 99%

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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Cisplatin is a highly successful and widely used chemotherapy for the treatment of various solid malignancies in both adult and pediatric patients. Side effects of cisplatin treatment include nephrotoxicity and ototoxicity. Cisplatin ototoxicity results from damage to and death of cells in the inner ear, including sensory hair cells. We showed previously that heat shock inhibits cisplatin-induced hair cell death in whole-organ cultures of utricles from adult mice. Since heat shock protein 70 (HSP70) is the most upregulated HSP in response to heat shock, we investigated the role of HSP70 as a potential protectant against cisplatin-induced hair cell death. Our data using utricles from HSP70 −/− mice indicate that HSP70 is necessary for the protective effect of heat shock against cisplatin-induced hair cell death. In addition, constitutive expression of inducible HSP70 offered modest protection against cisplatin-induced hair cell death. We also examined a second heat-inducible protein, heme oxygenase-1 (HO-1, also called HSP32). HO-1 is an enzyme responsible for the catabolism of free heme. We previously showed that induction of HO-1 using cobalt protoporphyrin IX (CoPPIX) inhibits aminoglycoside-induced hair cell death. Here, we show that HO-1 also offers significant protection against cisplatin-induced hair cell death. HO-1 induction occurred primarily in resident macrophages, with no detectable expression in hair cells or supporting cells. Depletion of macrophages from utricles abolished the protective effect of HO-1 induction. Together, our data indicate that HSP induction protects against cisplatin-induced hair cell death, and they suggest that resident macrophages mediate the protective effect of HO-1 induction.

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Section: Discussionmentioning

confidence: 99%

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Baker

Roy

Brandon

et al. 2014

JARO

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“…MAL3-101 was the product of a tandem MCR process under investigation in the Wipf and UPCMLD labs, combining the heterocyclic scaffold of the Biginelli-derived pyrimidinones with the large side-chain diversity accessible by Ugi four-component condensations. The availability of this probe enabled the interrogation of Hsp70's role in physiological and pathophysiological pathways by numerous laboratories (27)(28)(29). Based on these studies, the UPCMLD designed and synthesized second-and third-generation libraries using MAL3-101 as a lead in an effort to improve potency, understand the structural requirements for Hsp70 modulating activity, and improve physical properties.…”

Section: Resultsmentioning

confidence: 99%

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

Huryn

Brodsky

Brummond

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Unique chemical methodology enables the synthesis of innovative and diverse scaffolds and chemotypes and allows access to previously unexplored "chemical space." Compound collections based on such new synthetic methods can provide small-molecule probes of proteins and/or pathways whose functions are not fully understood. We describe the identification, characterization, and evolution of two such probes. In one example, a pathway-based screen for DNA damage checkpoint inhibitors identified a compound, MARPIN (ATM and ATR pathway inhibitor) that sensitizes p53-deficient cells to DNA-damaging agents. Modification of the small molecule and generation of an immobilized probe were used to selectively bind putative protein target(s) responsible for the observed activity. The second example describes a focused library approach that relied on tandem multicomponent reaction methodologies to afford a series of modulators of the heat shock protein 70 (Hsp70) molecular chaperone. The synthesis of libraries based on the structure of MAL3-101 generated a collection of chemotypes, each modulating Hsp70 function, but exhibiting divergent pharmacological activities. For example, probes that compromise the replication of a disease-associated polyomavirus were identified. These projects highlight the importance of chemical methodology development as a source of small-molecule probes and as a drug discovery starting point.ATPase | diversity oriented synthesis | isosteres | UPCMLD | alpha-methylene cyclopentenone

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“…The vital role of these proteins in many aspects of cellular functions has led to the development of small molecule inhibitors targeting chaperones for use as anti-cancer agents (1)(2)(3)(4) and therapeutics for neurodegenerative disorders (5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

Fontaine¹,

Martin²,

Akoury³

et al. 2015

Human Molecular Genetics

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The pathological accumulation of abnormally hyperphosphorylated and aggregated tau, a neuronal microtubule (MT)-associated protein that functions to maintain MT stability, is implicated in a number of hereditary and sporadic neurodegenerative diseases including frontotemporal dementia and Alzheimer's disease. Targeting tau for the treatment of these diseases is an area of intense interest and toward that end, modulation of cellular molecular chaperones is a potential therapeutic target. In particular, the constitutive Hsp70 isoform, Hsc70, seems highly interconnected with tau, preserving tau protein levels and synergizing with it to assemble MTs. But the relationship between tau and Hsc70, as well as the impact of this interaction in neurons and its therapeutic implications remain unknown. Using a human dominant negative Hsc70 that resembles isoform selective inhibition of this important chaperone, we found for the first time that Hsc70 activity is required to stimulate MT assembly in cells and brain. However, surprisingly, active Hsc70 also requires active tau to regulate MT assembly in vivo, suggesting that tau acts in some ways as a co-chaperone for Hsc70 to coordinate MT assembly. This was despite tau binding to Hsc70 as substrate, as determined biochemically. Moreover, we show that while chronic Hsc70 inhibition damaged MT dynamics, intermittent treatment with a small molecule Hsp70 inhibitor lowered tau in brain tissue without disrupting MT integrity. Thus, in tauopathies, where MT injury would be detrimental to neurons, the unique relationship of tau with the Hsc70 machinery can be exploited to deplete tau levels without damaging MT networks.

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Selective compounds define Hsp90 as a major inhibitor of apoptosis in small-cell lung cancer

Cited by 148 publications

References 38 publications

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

Chemical methodology as a source of small-molecule checkpoint inhibitors and heat shock protein 70 (Hsp70) modulators

The active Hsc70/tau complex can be exploited to enhance tau turnover without damaging microtubule dynamics

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