Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90

Kunicki, Joseph B.; Petersen, Mark N.; Alexander, Leslie D.; Ardi, Veronica C.; McConnell, Jeanette R.; McAlpine, Shelli R.

doi:10.1016/j.bmcl.2011.06.083

Cited by 38 publications

(51 citation statements)

References 24 publications

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“…31, 41 Indeed, six of seven TPR-containing proteins are inhibited by 0.5–1 μM of SM145, which is below SM145’s IC 50 value. By comparison, 17-AAG only partially inhibits FKBP51 and TOM70 at 5μM (Figure 5b), despite 17-AAG’s IC 50 being ~100nM.…”

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confidence: 88%

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

McConnell

Alexander

McAlpine

2014

Bioorganic & Medicinal Chemistry Letters

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When a cell encounters external stressors, such as lack of nutrients, elevated temperatures, changes in pH or other stressful environments, a key set of evolutionarily conserved proteins, the heat shock proteins (hsps), become overexpressed. Hsps are classified into six major families with the hsp90 family being the best understood; an increase in cell stress leads to increased levels of hsp90, which leads to cellular protection. A hallmark of hsp90 inhibitors is that they induce a cell rescue mechanism, the heat shock response. We define the unique molecular profile of a compound (SM145) that regulates hormone receptor protein levels through hsp90 inhibition without inducing the heat shock response. Modulation of the binding event between heat shock protein 90 and the immunophilins/homologs using SM145, leads to a decrease in hormone receptor protein levels. Unlike N-terminal hsp90 inhibitors, this hsp90 inhibitor does not induce a heat shock response. This work is proof of principle that controlling hormone receptor expression can occur by inhibiting hsp90 without inducing pro-survival protein heat shock protein 70 (hsp70) or other proteins associated with the heat shock response. Innovatively, we show that blocking the heat shock response, in addition to hsp90, is key to regulating hsp90-associated pathways.

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confidence: 88%

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

McConnell

Alexander

McAlpine

2014

Bioorganic & Medicinal Chemistry Letters

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“…45 Homodimerisation is the active conformation of Hsp90, which has led to the C-terminal dimerisation domain (with its nucleotide binding site and MEEVD co-chaperone binding region) becoming the focus of several Hsp90 inhibitors: Class IV (SM122 and 145), which show excellent Hsp90 inhibitory activity. [23][24][25][26][27]29,46 All four classes appear to modulate the allosteric cross talk between the N-and C-termini of Hsp90. However, each macrocyclic class of compounds impacts the clients and co-chaperone binding events uniquely.…”

Section: Macrocycles As Anticancer Agentsmentioning

confidence: 99%

“…Similarly, isoxazoles, triazoles and benzisoxazole resorcinols were also potent Hsp90 inhibitors. 56,[125][126][127] There are currently four related compounds in the clinic, including NVP-AU922, 26, an intravenous drug from Vernalis-Novartis, currently in Phase II trials, and Synta's ganetespib (27), also administered intravenously, which has been evaluated in the clinic against advanced solid tumours and was progressed to Phase III clinical trials against non-small cell lung carcinoma. 96 …”

Section: Radicicol-inspired Pyrazoles and Oxazolesmentioning

confidence: 99%

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Recent Advances in Macrocyclic Hsp90 Inhibitors

Ramsey

Kitson

Levin

et al. 2014

Macrocycles in Drug Discovery

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Natural products were the first compounds to confirm the advantages of cyclised structures, where the ring conformation provides structural stability and chemical potency. Successful clinical applications of macrocyclic compounds in oncology have produced powerful incentives within the medicinal chemistry community to explore macrocyclic drug candidates that target novel oncogenic pathways. Numerous receptors, signalling molecules, and enzymes involved in oncogenesis require the chaperone activity of heat shock protein 90 (Hsp90), an ATPase-driven dimer whose chief molecular roles involve protein folding and stabilisation. Herein we describe four classes of macrocyclic Hsp90 inhibitors. Class I macrocyclic anticancer agents, currently in clinical trials, target the ATP-binding pocket of Hsp90 and include synthetic derivatives of the ansamycin antibiotic geldanamycin (17-AAG or tanespimycin, 17-DMAG or alvespimycin, IPI-504 or retaspimycin). Class II inhibitors (radicicol, radanamycin), which also target the ATP-binding pocket of Hsp90, demonstrate greater potency than Class I inhibitors in preclinical studies, and recent improvements incorporated into synthetic derivatives and chimeras have led to greater structural stability than class I without loss of potency. Class III features synthetic derivatives targeting Hsp90's ATPase activity (o-aminobenzamides and aminopyrimidines), with promising clinical data pointing to these scaffolds as the next generation of therapeutic Hsp90 inhibitors. Class IV compounds are allosteric inhibitors that bind to the N-middle domain of Hsp90 and block access to proteins that bind the C-terminus of Hsp90 (SM122 and SM145). This final class is unique as it does not target the ATP binding site of Hsp90, thereby avoiding induction of the heat shock response. Development of compounds that modulate Hsp90's C-terminus may prove to be an effective method of avoiding the rescue response mounted when blocking the ATP-ase activity of Hsp90.

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“…Hsp90 is a ubiquitous molecular chaperone that regulates over 200 client proteins involved in multiple growth and signaling pathways. 3, 4, 6, 7 The roles of Hsp90 in these pathways include: regulating the conformational folding of numerous signal transduction molecules, and refolding denatured proteins under stress conditions. 9, 10 Because many hormone receptors, kinases and signaling molecules involved in these pathways are targets for chemotherapeutic strategies, Hsp90’s role as a master regulator has made it an attractive candidate for drug development.…”

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An Hsp90 modulator that exhibits a unique mechanistic profile

Ramsey

McConnell

Alexander

et al. 2012

Bioorganic & Medicinal Chemistry Letters

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Described is the synthesis of two biotinylated derivatives of a cytotoxic macrocycle. Pull-down assays indicate that this macrocycle targets the N-middle domain of Hsp90. Untagged compound can effectively compete away tagged compound-Hsp90 protein complexes, confirming the binding specificity of the macrocycle for Hsp90. The macrocycle is similar in potency to other structurally-related analogs of Sansalvamide A (San A) and induces apoptosis via a caspase 3 mechanism. Unlike other San A derivatives, we show that the macrocycle does not inhibit binding between C-terminal client proteins and co-chaperones and Hsp90, suggesting that it has a unique mechanism of action.

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Synthesis and evaluation of biotinylated sansalvamide A analogs and their modulation of Hsp90

Cited by 38 publications

References 24 publications

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

A heat shock protein 90 inhibitor that modulates the immunophilins and regulates hormone receptors without inducing the heat shock response

Recent Advances in Macrocyclic Hsp90 Inhibitors

An Hsp90 modulator that exhibits a unique mechanistic profile

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