Affinity Purification Probes of Potential Use To Investigate the Endogenous Hsp70 Interactome in Cancer

Rodina, Anna; Taldone, Tony; Kang, Yanlong; Patel, Pallav D.; Koren, John; Yan, Pengrong; Gomes, Erica M. Da Gama; Yang, Chenghua; Patel, Maulik; Shrestha, Liza; Ochiana, Stefan O.; Santarossa, Cristina; Maharaj, Ronnie; Gozman, Alexander; Cox, Marc B.; Erdjument‐Bromage, Hediye; Hendrickson, Ronald C.; Cerchietti, Leandro; Melnick, Ari; Guzmán, Mónica L.; Chiosis, Gabriela

doi:10.1021/cb500256u

Cited by 22 publications

(36 citation statements)

References 24 publications

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“…13a). YK5 bound Hsp72 in lysates [159] and, consistent with the model, mutation of C267S reduced binding. This molecule inhibited ATPase and refolding activity in vitro, consistent with the functional importance of this allosteric site.…”

Section: Yk5supporting

confidence: 78%

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Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Srinivasan

Shao

et al. 2015

Topics in Medicinal Chemistry

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Cancer cells survive in the presence of stresses that would normally cause cell death. To accomplish this feat, they express elevated levels of the molecular chaperones: heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90). Knockdown of these chaperones is selectively toxic to cancer cells, suggesting that they might be promising nodes for anticancer therapy. However, while inhibitors of Hsp90 are well known, progress in the development of Hsp70 inhibitors has proven more difficult. Hsp70 binds tightly to ATP through a highly conserved domain of the actin/hexokinase superfamily, making it challenging to identify selective, competitive inhibitors. Despite this obstacle, progress has been made and first-generation molecules are being deployed. To supplement these efforts, compounds that target important allosteric sites on the chaperone have also been discovered. In some of these cases, the molecules have been shown to control key protein-protein interactions between Hsp70 and its co-chaperones. In other cases, allosteric sites have been used to gain unexpected selectivity for members of the Hsp70 family. Here, we review recent progress in the development of Hsp70 inhibitors.

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Section: Yk5supporting

confidence: 78%

“…Immobilized YK5 was used to ask an important question about Hsp70 function in cancer cells [159]. In SKBr3 cell extracts, YK5 was used to pull down cofactors of the chaperone, revealing Hsp110, Her2, cyclin D, and Raf1 as being Hsp70 bound.…”

Section: Yk5mentioning

confidence: 99%

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Srinivasan

Shao

et al. 2015

Topics in Medicinal Chemistry

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“…In cancer cells, both YK5 and TT9 altered the formation of a functional HSP70-HSP90 machinery and promoted the degradation of several of its onco-clients. Rodina et al took advantage of YK5 to design and develop an affinity purification chemical toolset for potential use in the investigation of the endogenous HSP70-interacting proteome in cancer (Rodina et al, 2014). A cell permeable YK5-biotin (Figure 3B) locked HSP70 in complex with onco-client proteins and effectively isolated HSP70 complexes for identification through biochemical techniques.…”

Section: Hsp70 Probesmentioning

confidence: 99%

Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease

Shrestha

Patel

Chiosis

2016

Cell Chemical Biology

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The chaperome is a large and diverse protein machinery composed of chaperone proteins and a variety of helpers, such as the co-chaperones, folding enzymes and scaffolding and adapter proteins. Heat shock protein 90s and 70s (HSP90s and HSP70s), the most abundant chaperome members in human cells, are also the most complex. As we have learned to appreciate, their functions are context dependent and manifested through a variety of conformations that each recruit a subset of co-chaperone, scaffolding and folding proteins and which are further diversified by the post-translational modifications each carry, making their study through classic genetic and biochemical techniques quite a challenge. Chemical biology tools and techniques have been developed over the years to help decipher the complexities of the HSPs and this review will provide an overview of such efforts with focus on HSP90 and HSP70.

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“…By chemically sensing the stress chaperome one may investigate its associated, disease-causing, proteome and thus investigate mechanisms associated with and causing the stress state [8, 28, 31, 32, 40]. By using small molecules selectively targeting the stress chaperome species as affinity-purification baits [8, 63, 64] or as global perturbers of the altered proteome [65], one may inquire into its nature, i.e. identify.…”

Section: Targeting the Stress Chaperome Lessons From Hsp90mentioning

confidence: 99%

Selective targeting of the stress chaperome as a therapeutic strategy

Taldone

Ochiana

Patel

et al. 2014

Trends in Pharmacological Sciences

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104

137

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Normal cellular function is maintained by coordinated proteome machinery that performs a vast array of activities. Helping the proteome in such roles is the chaperome, a network of molecular chaperones and folding enzymes. The stressed cell contains, at any time, a complex mixture of chaperome complexes; a majority performs “housekeeping functions” similarly to non-stressed, normal cells, but a finely-tuned fraction buffers the proteome altered by chronic stress. The stress chaperome is epigenetically distinct from its normal, housekeeping counterpart, providing a basis for its selective targeting by small molecules. Here we discuss development of chaperome inhibitors, and how agents targeting chaperome members in stressed cells are in fact being directed towards chaperome complexes and their effect is therefore determined by their ability to sample and engage such complexes. A new approach is needed to target and implement chaperome modulators in the investigation of diseases, and we propose that the classical thinking in drug discovery needs adjustment when developing chaperome-targeting drugs.

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Affinity Purification Probes of Potential Use To Investigate the Endogenous Hsp70 Interactome in Cancer

Cited by 22 publications

References 24 publications

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

Chemical Tools to Investigate Mechanisms Associated with HSP90 and HSP70 in Disease

Selective targeting of the stress chaperome as a therapeutic strategy

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