Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)

Brasca, Maria Gabriella; Mantegani, Sergio; Amboldi, Nadia; Bindi, Simona; Caronni, Dannica; Casale, Elena; Ceccarelli, Walter; Colombo, Nicoletta; Ponti, Anna De; Donati, Daniele; Ermoli, Antonella; Fachin, Gabriele; Felder, E.; Ferguson, R. D.; Fiorelli, Claudio; Guanci, Marco; Isacchi, Antonella; Pesenti, Enrico; Polucci, Paolo; Riceputi, Laura; Sola, Francesco; Visco, Carlo; Zuccotto, Fabio; Fogliatto, Gianpaolo

doi:10.1016/j.bmc.2013.09.018

Cited by 25 publications

(24 citation statements)

References 41 publications

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“…It induced HER2 degradation (IC 50 = 0.11 μM) and inhibited the proliferation of A2780 ovarian cancer cells (IC 50 = 0.06 μM). Compound 92 showed favorable solubility in water at pH 7 (179 μM) [105]. When administered intravenously at 30 and 60 mg/kg to mice bearing A2780 tumors for 10 consecutive days, compound 92 resulted in a tumor growth inhibition of 53 and 74%, respectively.…”

Section: Hsp90 Inhibitorsmentioning

confidence: 99%

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: 99%

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

Taldone

Patel

Bolaender

et al. 2014

Expert Opinion on Therapeutic Patents

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“…Heat shock protein 90 (Hsp90) is a molecular chaperone, which plays a key role in signal transduction pathways, whose inhibition has been widely described as one of the potential cancer's treatments. 34 Tumor necrosis factor receptorassociated protein 1 (TRAP1), a member of the HSP90 family, is involved in several physiological functions, including cell proliferation, differentiation, and survival. The anti-apoptotic roles of TRAP1 were explored as an important target for anticancer drug development and for tumor control in clinical settings.…”

Section: Molecular Modelingmentioning

confidence: 99%

“…The anti-apoptotic roles of TRAP1 were explored as an important target for anticancer drug development and for tumor control in clinical settings. 34 Therefore, the mitochondrial pool of Hsp90 and its mitochondrial paralogue, TRAP1, have been studied as target proteins for anticancer drug development. 35 Our compounds showed affinity to the heat shock proteins TRAP1 in silico and this could be a potential mode of action that explain the compounds antiproliferative activities.…”

Section: Molecular Modelingmentioning

confidence: 99%

Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells

et al. 2020

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“…Namely, Hsp90 inhibitors suppressed growth of human cancer cell lines , . Some of these compounds are currently undergoing clinical evaluation as anticancer agents . However, biological effects of isomeric 3,4‐diarylisoxazole‐5‐carboxamides (Figure , B) were less investigated due to the challenges in regioselective synthesis and the lack of efficient synthetic routes for their intermediates, 3,4‐diarylisoxazoline N‐oxides.…”

Section: Introductionmentioning

confidence: 99%

Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

et al. 2019

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A simple scalable procedure for the synthesis of 3,4‐diaryl‐isoxazole‐5‐carboxamides 6 under mild conditions from readily available material was developed. The targeted compounds 6, structural analogues of heat shock protein inhibitors, were obtained by the rearrangement of intermediate 3,4‐diaryl‐5‐carboxamido‐isoxazoline N‐oxides 5. In contrast to carboxamido‐isoxazoline oxides 5, base‐catalyzed recyclization of 3,4‐diaryl‐5‐(ethoxycarbonyl)isoxazoline N‐oxides 9c unexpectedly yielded 5‐hydroxy‐1,2‐oxazin‐6‐ones 17c instead of ethyl 3,4‐diaryl‐isoxazole‐5‐carboxylates 10. Crystal and molecular structure of 4‐(2,5‐dimethoxy‐3,4‐methylenedioxyphenyl)‐5‐hydroxy‐3‐phenyl‐6H‐1,2‐oxazin‐6‐one 17c was established by single‐crystal X‐ray diffraction study. In a phenotypic sea urchin embryo assay, carboxamide 6f showed moderate antimitotic antitubulin activity compared to 5‐unsubstituted 3,4‐diarylisoxazoles 15, which featured strong microtubule destabilizing effect.

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Discovery of NMS-E973 as novel, selective and potent inhibitor of heat shock protein 90 (Hsp90)

Cited by 25 publications

References 41 publications

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

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

Newly synthesized 3-(4-chloro-phenyl)-3-hydroxy-2,2-dimethyl-propionic acid methyl ester derivatives selectively inhibit the proliferation of colon cancer cells

Effective Synthesis of 3,4‐Diaryl‐isoxazole‐5‐carboxamides and their Antiproliferative Properties

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