EC144 Is a Potent Inhibitor of the Heat Shock Protein 90

Shi, Jiandong; Water, Ryan Van de; Hong, Kevin; Lamer, Ryan B; Weichert, Kenneth; Sandoval, Cristina M; Kasibhatla, Srinivas Rao; Boehm, Marcus F.; Chao, Jianhua; Lundgren, Karen; Timple, Noelito; Lough, Rachel; Ibanez, Gerardo; Boykin, Christina; Burrows, Francis; Kehry, Marilyn R.; Yun, Theodore J.; Harning, Erin; Ambrose, Christine; Thompson, Jeffrey S.; Bixler, Sarah A.; Dunah, Anthone W.; Snodgrass-Belt, Pamela; Arndt, Joseph W.; Enyedy, Istvan; Li, Ping; Hong, Victor Sukbong; McKenzie, Andres; Biamonte, Marco A.

doi:10.1021/jm300810x

Cited by 61 publications

(52 citation statements)

References 42 publications

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“…The susceptibility of compound 45 to hydrolysis suggests that the acid may be the active form in cells. These compounds appear to be similar to a series of pyrrolopyrimidines previously claimed in a patent by Conforma Therapeutics in 2006, which contained EC144 (46), an orally available compound that induced HER2 degradation (i.e., a functional read-out of Hsp90 inhibition in cancer cells) with an EC 50 = 14 nM (Figure 4) [73,74]. …”

Section: Hsp90 Inhibitorsmentioning

confidence: 71%

Protein chaperones: a composition of matter review (2008 – 2013)

Taldone

Patel

Bolaender

et al. 2014

Expert Opinion on Therapeutic Patents

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Introduction Heat shock proteins (Hsps) are proteins with important functions in regulating disease phenotypes. Historically, Hsp90 has first received recognition as a target in cancer, with consequent efforts extending its potential role to other diseases. Hsp70 has also attracted interest as a therapeutic target for its role as a co-chaperone to Hsp90 as well as its own anti-apoptotic roles. Areas covered Herein, patents from 2008 to 2013 are reviewed to identify those that disclose composition of matter claimed to inhibit Hsp90 or Hsp70. Expert opinion For Hsp90, there has been considerable creativity in the discovery of novel pharmacophores that fall outside the three initially discovered scaffolds (i.e., ansamycins, resorcinols and purines). Nonetheless, much of the patent literature appears to build on previously reported structure activity relationship through slight modifications of Hsp90 inhibitor space by finding weaknesses in existing patents. The major goal of future development of Hsp90 inhibitors is not necessarily identifying better molecules but rather understanding how to rationally use these agents in the clinic. The development of Hsp70 inhibitors has lagged behind. It will require a more concerted effort from the drug discovery community in order to begin to realize the potential of this target.

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Section: Hsp90 Inhibitorsmentioning

confidence: 71%

Protein chaperones: a composition of matter review (2008 – 2013)

Taldone

Patel

Bolaender

et al. 2014

Expert Opinion on Therapeutic Patents

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“…The precise location and reversible mode of binding for each inhibitor (or a closely related analogue; i.e., geldanamycin for 17-AAG 17 and an earlier lead compound for NVP-AUY922 19 ) has been confirmed through X-ray crystallographic analysis of cocrystal structures. 20,21 Like ATP itself, each compound inhibited probe labeling of both domains in a dose-dependent manner ( Figure 3B). These data revealed clear differences in both overall potency and paralog specificity among the set of compounds.…”

Section: ■ Resultsmentioning

confidence: 94%

ATP Acyl Phosphate Reactivity Reveals Native Conformations of Hsp90 Paralogs and Inhibitor Target Engagement

Nordin¹,

Liu²,

Aban³

et al. 2015

Biochemistry

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Hsp90 is an ATP-dependent chaperone of widespread interest as a drug target. Here, using an LC-MS/MS chemoproteomics platform based on a lysine-reactive ATP acyl phosphate probe, several Hsp90 inhibitors were profiled in native cell lysates. Inhibitor specificities for all four human paralogs of Hsp90 were simultaneously monitored at their endogenous relative abundances. Equipotent inhibition of probe labeling in each paralog occurred at sites both proximal to and distal from bound ATP observed in Hsp90 cocrystal structures, suggesting that the ATP probe is assaying a native conformation not predicted by available structures. Inhibitor profiling against a comprehensive panel of protein kinases and other ATP-binding proteins detected in native cell lysates identified PMS2, a member of the GHKL ATPase superfamily as an off-target of NVP-AUY922 and radicicol. Because of the endogenously high levels of Hsp90 paralogs in typical cell lysates, the measured potency of inhibitors was weaker than published IC₅₀ values. Significant inhibition of Hsp90 required inhibitor concentrations above a threshold where off-target activity was detectable. Direct on- and off-target engagement was measured by profiling lysates derived from cells treated with Hsp90 inhibitors. These studies also assessed the downstream cellular pathway effects of Hsp90 inhibition, including the down regulation of several known Hsp90 client proteins and some previously unknown client proteins. Overall, the ATP probe-based assay methodology enabled a broad characterization of Hsp90 inhibitor activity and specificity in native cell lysates.

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“…Third, there are numerous Hsp90 inhibitor chemotypes for which extensive chemistry has been developed and binding to Hsp90 revealed by crystallography, and therefore the choice for the FP probe and knowledge over the site of its fluorescence labeling is available. 21–23,37–44 To date, however, no FP assay that efficiently tests for affinity and selectivity of small molecules to all four Hsp90 paralogues has been reported.…”

Section: Resultsmentioning

confidence: 99%

Experimental and Structural Testing Module to Analyze Paralogue-Specificity and Affinity in the Hsp90 Inhibitors Series

Taldone

Patel

et al. 2013

J. Med. Chem.

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We here describe the first reported comprehensive analysis of Hsp90 paralogue affinity and selectivity in the clinical Hsp90 inhibitor chemotypes. This has been possible through the development of a versatile experimental assay based on a new FP-probe (16a) that we both describe here. The assay can test rapidly and accurately the binding affinity of all major Hsp90 chemotypes and has a testing range that spans low nanomolar to millimolar binding affinities. We couple this assay with a computational analysis that allows for rationalization of paralogue selectivity and defines not only the major binding modes that relay pan-paralogue binding or, conversely, paralogue selectivity, but also identifies molecular characteristics that impart such features. The methods developed here provide a blueprint for parsing out the contribution of the four Hsp90 paralogues to the perceived biological activity with the current Hsp90 chemotypes and set the ground for the development of paralogue selective inhibitors.

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EC144 Is a Potent Inhibitor of the Heat Shock Protein 90

Cited by 61 publications

References 42 publications

Protein chaperones: a composition of matter review (2008 – 2013)

Protein chaperones: a composition of matter review (2008 – 2013)

ATP Acyl Phosphate Reactivity Reveals Native Conformations of Hsp90 Paralogs and Inhibitor Target Engagement

Experimental and Structural Testing Module to Analyze Paralogue-Specificity and Affinity in the Hsp90 Inhibitors Series

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