Hsp90 as a Target for Drug Development

Chaudhury, Subhabrata; Welch, Timothy R.; Blagg, Brian S. J.

doi:10.1002/chin.200712277

Cited by 7 publications

(7 citation statements)

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“…Among Hsp90’s are key anti-apoptotic proteins, including Akt, Cdk4, Raf1 and Her2 71, 72. Inhibiting the binding of Hsp90 to ATP leads to proteasomal degradation of these substrates and corresponding anti-proliferative activity 50, 73, 74. In the context of our discussion, treatment with Hsp90 inhibitors has also been found to induce expression of Hsp70, likely through activation of HSF1 70.…”

Section: Roles Of Hsp70 In Diseasementioning

confidence: 69%

Heat Shock Protein 70 (Hsp70) as an Emerging Drug Target

2010

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Heat shock protein 70 (Hsp70) is a molecular chaperone that is expressed in response to stress. In this role, Hsp70 binds to its protein substrates and stabilize them against denaturation or aggregation until conditions improve.1 In addition to its functions during a stress response, Hsp70 has multiple responsibilities during normal growth; it assists in the folding of newly synthesized proteins,2 , 3 the subcellular transport of proteins and vesicles,4 the formation and dissociation of complexes,5 and the degradation of unwanted proteins.6 , 7 Thus, this chaperone broadly shapes protein homeostasis by controlling protein quality control and turnover during both normal and stress conditions.8 Consistent with these diverse activities, genetic and biochemical studies have implicated it in a range of diseases, including cancer, neurodegeneration, allograft rejection and infection. This review provides a brief review of Hsp70 structure and function and then explores some of the emerging opportunities (and challenges) for drug discovery. Hsp70 is Highly ConservedMembers of the Hsp70 family are ubiquitously expressed and highly conserved; for example, the major Hsp70 from Escherichia coli, termed DnaK, is approximately 50% identical to human Hsp70s.9 Eukaryotes often express multiple Hsp70 family members with major isoforms found in all the cellular compartments: Hsp72 (HSPA1A) and heat shock cognate 70 (Hsc70/HSPA8) in the cytosol and nucleus, BiP (Grp78/HSPA5) in the endoplasmic reticulum and mtHsp70 (Grp75/mortalin/HSPA9) in mitochondria. Some of the functions of the cytosolic isoforms, Hsc70 and Hsp72, are thought to be redundant, but the transcription of Hsp72 is highly responsive to stress and Hsc70 is constitutively expressed. In the ER and mitochondria, the Hsp70 family members are thought to fulfill specific functions and have unique substrates, with BiP playing key roles in the folding and quality control of ER proteins and mtHsp70 being involved in the import and export of proteins from the mitochondria. For the purposes of this review, we will often use Hsp70 as a generic term to encompass the shared properties of the family members. Domain Architecture and Substrate Binding of Hsp70All members of the Hsp70 family have an N-terminal nucleotide binding domain (NBD) (~40 kDa) and a C-terminal substrate-binding domain (SBD) (~25 kDa) connected by a short linker ( Figure 1A).10 The NBD consists of two subdomains, I and II, which are further divided into regions a and b. The Ia and IIa subdomains interact with ATP through a nucleotide-binding cassette related to those of hexokinase, actin and glycerol kinase.11 , 12 The SBD consists of a 10-kDa α-helix subdomain and a 15-kDa β-sandwich. Crystal structures suggest that substrate peptides are bound in an extended conformation between * Correspondence can be addressed to: Jason E. Gestwicki, University of Michigan, Life Sciences Institute, 210 Washtenaw Ave, Ann Arbor, MI 48109-2216, P (734) 615-9537, gestwick@umich.edu. loops of the β-sandwich and that the α-heli...

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Section: Roles Of Hsp70 In Diseasementioning

confidence: 69%

Heat Shock Protein 70 (Hsp70) as an Emerging Drug Target

2010

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“…HSP90 is reported to be a chemotherapeutic target molecule for many cancers, including CML 35,36,48,52. Some of the critical signaling molecules in Bcr-Abl+ cells are client proteins of HSP90 14,47,3.…”

Section: Resultsmentioning

confidence: 99%

Destabilization of Bcr-Abl/Jak2 Network by a Jak2/Abl Kinase Inhibitor ON044580 Overcomes Drug Resistance in Blast Crisis Chronic Myelogenous Leukemia (CML)

et al. 2010

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Bcr-Abl is the predominant therapeutic target in chronic myeloid leukemia (CML), and tyrosine kinase inhibitors (TKIs) that inhibit Bcr-Abl have been successful in treating CML. With progression of CML disease especially in blast crisis stage, cells from CML patients become resistant to imatinib mesylate (IM) and other TKIs, resulting in relapse. Because Bcr-Abl is known to drive multiple signaling pathways, the study of the regulation of stability of Bcr-Abl in IM-resistant CML cells is a critical issue as a possible therapeutic strategy. Here, we report that a new dual-kinase chemical inhibitor, ON044580, induced apoptosis of Bcr-Abl+ IM-sensitive, IM-resistant cells, including the gatekeeper Bcr-Abl mutant, T315I, and also cells from blast crisis patients. In addition, IM-resistant K562-R cells, cells from blast crisis CML patients, and all IM-resistant cell lines tested had reduced ability to form colonies in soft agar in the presence of 0.5 µM ON044580. In in vitro kinase assays, ON044580 inhibited the recombinant Jak2 and Abl kinase activities when the respective Jak2 and Abl peptides were used as substrates. Incubation of the Bcr-Abl+ cells with ON044580 rapidly reduced the levels of the Bcr-Abl protein and also reduced the expression of HSP90 and its client protein levels. Lysates of Bcr-Abl+ cell lines were found to contain a large signaling network complex composed of Bcr-Abl, Jak2, HSP90, and its client proteins as detected by a gel filtration column chromatography, which was rapidly disrupted by ON044580. Therefore, targeting Jak2 and Bcr-Abl kinases is an effective way to destabilize Bcr-Abl and its network complex, which leads to the onset of apoptosis in IM-sensitive and IM-resistant Bcr-Abl+ cells. This inhibitory strategy has potential to manage all types of drug-resistant CML cells, especially at the terminal blast crisis stage of CML, where TKIs are not clinically useful.

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“…Recent studies have revealed that Hsp90 inhibitors accumulate in tumor cells more efficiently than in normal tissue leading to high differential selectivities 18,19. Currently, there are 26 Hsp90-targeted clinical trials in progress and these studies have demonstrated that Hsp90 can be inhibited at doses that are well tolerated by patients 20-23. Consequently, Hsp90 has emerged as a promising therapeutic target for the treatment of cancer because inhibition of Hsp90 results in the simultaneous degradation of multiple anti-cancer targets 11-14,23-24…”

Section: Discussionmentioning

confidence: 99%