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Heat Shock Protein 90 (Hsp90) Inhibitory Potentials of Some Chalcone Compounds as Novel Anti-Proliferative Candidates
Published in P. Mereena Luke, K. R. Dhanya, Didier Rouxel, Nandakumar Kalarikkal, Sabu Thomas, Advanced Studies in Experimental and Clinical Medicine, 2021
Debarshi Kar Mahapatra, Sayan Dutta Gupta, Sanjay Kumar Bharti, Tomy Muringayil Joseph, Józef T. Haponiuk, Sabu Thomas
Hsp90 carries out its chaperoning function with the aid of ATP and co-chaperones (Figure 5.2). ATP provides the required energy for the entire chaperoning process by hydrolyzing to ADP and phosphate [19]. The process starts with the binding of client protein to Hsp90’s middle domain with the help of co-chaperones [20]. Thereafter, the ATP binds to the N domain of the chaperone, resulting in the dimerization of the N and M segments [21]. The N and M domain then comes in contact with one another, which leads to the generation of Hsp90’s “closed form” configuration [22]. The ATP hydrolysis and client protein repairing take place in this closed configuration of Hsp90. Thereafter, ADP, phosphate, and the repaired client protein are released from the protein complex [23]. It was also observed that sometimes ATP first attaches itself to the chaperone’s N-terminal Bergerat fold and thereafter the client polypeptides bind to Hsp90 with co-chaperones [24]. This is followed by the usual chaperoning cycle, i.e., attainment of the closed-state, hydro-lysis of ATP, repair of proteins, and release of ATP and matured proteomes [25] (Figure 5.3).
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
As cancer cells, due to their genetic mutations, typically contain a large number of proteins that do not fold properly, they often compensate by over-expressing HSP90. The result is that even mutated proteins usually fold sufficiently well to avoid disposal by the proteasomes, thus allowing cancer cells to survive. Therefore, inhibiting the activity of HSP90 should lead to a reduction in folding activity in all cells, with more client proteins being destroyed by the proteasomes. However, because cancer cells have a higher dependence on HSP90 than normal cells (i.e., as they have more mutated proteins to deal with), HSP90 is considered a good target for drug intervention. Furthermore, as it is involved in the correct functioning of so many oncoproteins and pathways (including signal transduction and transcription), inhibition of HSP90 should block multiple oncogenic pathways in cancer cells, a preferable strategy compared with targeting a single point of vulnerability. Therefore, this type of “combinatorial blockade” of oncogenic targets may inhibit all of the hallmark traits of malignancy (see Chapter 1), and so has the potential for broad-spectrum clinical activity across multiple cancer types. However, there is a risk of serious adverse effects with inhibitors of this type as HSP90 is also involved in normal cell functioning.
Tyrosine Kinase Inhibitors: Targets Other Than FLT3, BCR-ABL, and c-KIT
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Suzanne R. Hayman, Judith E. Karp
Hsp90 is an ATP-dependent molecular chaperone that is localized primarily in the cytosol, has homologs in the endoplasmic reticulum and mitochondria, and acts as the cornerstone of a heteroprotein complex that exists in both active and quiescent states depending upon ATP hydrolysis and ADP/ATP nucleotide exchange (4). Hsp90 client proteins initially interact with an Hsp70/Hsp40 complex that is linked subsequently to the ADP-bound conformation of Hsp90 by p60HOP. The replacement of Hsp90 ADP by ATP changes the Hsp90 conformation, which results in the release of p60HOP and Hsp70/Hsp40 and allows for recruitment of other cochaperones including p23, certain immunophilins, or p50Cdc37 (5). This ATP-Hsp90 conformation allows for the appropriate folding and stabilization of client proteins. This chaperone complex associates with and participates in the folding, conformational maturation, and regulation of multiple client signal transduction proteins, either by protecting them from or targeting them for ubiquitination and proteosomal degradation on the basis of the nucleotide conformation within the Hsp90 amino terminus ATP/ADP binding site (6).
Design, synthesis, biological evaluation and molecular docking study of 2,4-diarylimidazoles and 2,4-bis(benzyloxy)-5-arylpyrimidines as novel HSP90 N-terminal inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Man Yang, Chenyao Li, Yajing Li, Chen Cheng, Meiyun Shi, Lei Yin, Hongyu Xue, Yajun Liu
Because proteins play roles in nearly every cellular process, it is essential to maintain protein homeostasis to preserve normal cell functions. Molecular chaperones are a large family of proteins that guard cellular protein homeostasis by regulating the conformation and quality of client proteins1,2. Heat shock protein 90 (HSP90) is one of the most crucial molecular chaperones in eukaryotes and stabilises and activates more than 400 client proteins3,4. Because cancer cells require higher levels of proteins for survival than normal cells, HSP90 is overexpressed in cancer cells, accounting for 4–6% of the whole proteome5,6. In addition, conformations of normal HSP90 and HSP90 of the cancer phenotype are different, and the latter is more susceptible to inhibitors7. Inhibition of HSP90 in cancer cells results in the degradation of client oncoproteins via the ubiquitin-proteasome pathway and the subsequent disruption of multiple signal transduction pathways, further leading to the apoptosis of cancer cells8,9. Therefore, HSP90 is a promising therapeutic target for discovering anticancer drugs10. Beyond cancer, HSP90 has also emerged as a potential drug target in other protein-related diseases, such as neurodegenerative diseases, infectious diseases, and ageing11–14.
Mitochondria targeting molecular transporters: synthesis, lipophilic effect, and ionic complex
Published in Drug Delivery, 2022
Akula S. N. Murthy, Sanket Das, Tejinder Singh, Tae-Wan Kim, Nasim Sepay, Seob Jeon, Jungkyun Im
Next, we tested the mitochondria drug targeting capability of the molecular transporter. Since the fluorescent probe was no longer necessary and needed to be replaced by a drug, G4-Nal without FITC was used. First, in vitro stability of G4-Nal in PBS and human plasma was studied. As shown in Figure S7, the percentage of intact G4-Nal was 93.6% in PBS and 81.3% in human plasma, demonstrating sufficient stability to reach mitochondria. Geldanamycin (GA) was used as a model cargo drug. GA is a well-known antitumor antibiotic that inhibits the function of heat shock protein 90 (Hsp90), which is a potential target for cancer therapy (Franke et al., 2013). Since it belongs to a family of molecular chaperones, Hsp90 helps stabilize numerous proteins inside cells to protect protein folding, preventing the apoptosis process. Moreover, mitochondrial Hsp90s are involved in cancer signaling networks that promote tumor development and metastasis (Kang et al., 2009). Since Hsp90s are overexpressed in cancerous cells, inhibition of Hsp90 in mitochondria can prevent disease progression and block the antiapoptotic nature of Hsp90.
Antitumour effects of a solid lipid nanoparticle loaded with gemcitabine and oxaliplatin on the viability, apoptosis, autophagy, and Hsp90 of ovarian cancer cells
Published in Journal of Microencapsulation, 2022
Ashwaq A. Al-Mutairi, Mayson H. Alkhatib
The Hsp90 is a molecular chaperone which is critical for maintaining the folding, assembly, and maturation of the native conformation of proteins (Galam et al. 2007). It was found that Hsp90 to be highly expressed in various cancerous tissues compared to the non-cancerous tissue (Yu et al. 2010). In the malignant cells, Hsp90 is overexpressed and is required to fold and maintain the activity of both native and mutated signal transduction proteins that are responsible for the uncontrolled cancer cell proliferation of transformed cells and survival (Moser et al. 2007). Consequently, inhibiting the Hsp90 activity emerged as a new target for anticancer agents. In this study, the blank SLN and the entire drug loaded SLN had markedly reduced Hsp90 concentration which could be attributed to the small sizes of SLN that lead to the cellular uptake enhancement by the ovarian cancer cells. The fact that Hsp90 is an interesting molecular target for cancer therapy has been reported and validated in various pre-clinical studies. Mellatyar et al. (2014) reported that 17-DMAG nanoparticles can be more effective than free 17DMAG in down-regulating of Hsp90 expression by enhancing the lung cancer cells uptake.