Mechanistic Studies of Sansalvamide A-Amide: An Allosteric Modulator of Hsp90

Vasko, Robert C.; Rodriguez, Rodrigo; Cunningham, Christian N.; Ardi, Veronica C.; Agard, David A.; McAlpine, Shelli R.

doi:10.1021/ml900003t

Cited by 95 publications

(110 citation statements)

References 37 publications

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“…Investigations done by McAlpine and co-workers utilizing the peptide analog of San A (SM1, Fig. 1) showed that this San A derivative targeted heat shock protein 90 (Hsp90) [22]. Hsp90 is a major molecular chaperone that is involved in the progression and survival of cancer cells.…”

Section: Sansalvamide Amentioning

confidence: 99%

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Wahyudi

McAlpine

2015

Bioorganic Chemistry

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Section: Sansalvamide Amentioning

confidence: 99%

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Wahyudi

McAlpine

2015

Bioorganic Chemistry

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“…This class of macrocyclic inhibitors allosterically modulate the C-terminus of Hsp90, and include the structures SM122 and SM145. [23][24][25][26][27][28][29] 2.1.2 Heat Shock Protein 90 (Hsp90) as an Oncogenic Target…”

Section: Macrocycles As Anticancer Agentsmentioning

confidence: 99%

“…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%

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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“…Complexes between Hsp90 and its co-chaperones are enriched in cancer cells [40], suggesting that the cancer-specific roles of Hsp90 may be linked to cooperation with these factors [41]. Indeed, sansalvamide A [42,43] and gedunin [34] are inhibitors of co-chaperone binding, and they are selectively toxic to cancer cells.…”

mentioning

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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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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Mechanistic Studies of Sansalvamide A-Amide: An Allosteric Modulator of Hsp90

Cited by 95 publications

References 37 publications

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Predicting the unpredictable: Recent structure–activity studies on peptide-based macrocycles

Recent Advances in Macrocyclic Hsp90 Inhibitors

Allosteric Inhibitors of Hsp70: Drugging the Second Chaperone of Tumorigenesis

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