The disruption of protein−protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition
| العنوان: | The disruption of protein−protein interactions with co-chaperones and client substrates as a strategy towards Hsp90 inhibition |
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| المؤلفون: | Brian S. J. Blagg, Michael A. Serwetnyk |
| المصدر: | Acta Pharmaceutica Sinica. B Acta Pharmaceutica Sinica B, Vol 11, Iss 6, Pp 1446-1468 (2021) |
| بيانات النشر: | Elsevier BV, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | MD, middle domain, Review, SUMO, small ubiquitin-like modifier, TPR2A, tetratricopeptide-containing repeat 2A, chemistry.chemical_compound, 0302 clinical medicine, Immunophilins, polycyclic compounds, General Pharmacology, Toxicology and Pharmaceutics, Natural products, 0303 health sciences, biology, Small molecules, HIF-1α, hypoxia-inducing factor-1α, HSQC, heteronuclear single quantum coherence, Geldanamycin, Hsp90, CTD, C-terminal domain, Radicicol, Cell biology, 030220 oncology & carcinogenesis, HOP, Hsp70‒Hsp90 organizing protein, SAHA, suberoylanilide hydroxamic acid, Protein folding, ATP, adenosine triphosphate, Cdc37, cell division cycle 37, RM1-950, Protein–protein interaction, 03 medical and health sciences, TROSY, transverse relaxation-optimized spectroscopy, Heat shock protein, SAR, structure–activity relationship, NTD, N-terminal domain, Heat shock, 030304 developmental biology, Disruptors, TRAP1, Hsp75tumor necrosis factor receptor associated protein 1, Hsp90, 90-kD heat shock protein, Her-2, human epidermal growth factor receptor-2, Aha1, activator of Hsp90 ATPase homologue 1, HIP, Hsp70-interaction protein, hERG, human ether-à-go-go-related gene, PPI, protein−protein interaction, ADP, adenosine diphosphate, chemistry, Grp94, 94-kD glucose-regulated protein, biology.protein, Protein−protein interactions, Therapeutics. Pharmacology, Peptidomimetics |
| الوصف: | The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous, ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates. Because many of these clients are overexpressed or become mutated during cancer progression, Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways simultaneously. The first discovered Hsp90 inhibitors, geldanamycin and radicicol, function by competitively binding to Hsp90's N-terminal binding site and inhibiting its ATPase activity. However, most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four isoforms. Consequently, alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition, isoform-selective inhibition, and the disruption of Hsp90 protein−protein interactions. Since the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex, along with various co-chaperones and immunophilins, the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition. Graphical abstract Many natural products and small molecules have been reported to disrupt protein–protein interactions (PPIs) between Hsp90 and its co-chaperones and client substrates. Such results offer support to the disruption of PPIs as an alternative strategy for selective inhibition of this molecular chaperone.Image 1 |
| تدمد: | 2211-3835 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d551031a93c74226093f0f0844e22506Test https://doi.org/10.1016/j.apsb.2020.11.015Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d551031a93c74226093f0f0844e22506 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22113835 |
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