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Novel Anti-Cancer Drugs Based On Hsp90 Inhibitory Mechanisms: A Recent Report
Published in Debarshi Kar Mahapatra, Sanjay Kumar Bharti, Medicinal Chemistry with Pharmaceutical Product Development, 2019
Derrubone (isolfavone isolated from Derris robusta) is another nature-based novel Hsp90 inhibitor that executes its action by blocking Cdc37-Hsp90 interaction [189]. Cdc37 is a co-chaperone involved in the recruitment of numerous Hsp90 client peptides (mainly kinases) [190, 191]. Hence, disruption of Cdc37-Hsp90 bonding leads to the degradation of numerous client proteins of Hsp90. However, the exact mode of inhibiting Hsp90-Cdc37 bondage is still not clearly elucidated. It is proposed that it carries out its function with the help of heme-regulated eIF2a kinase (HRI) kinase enzyme, a Hsp90 client [183, 189].
Cell division cycle 37 change after bortezomib-based induction therapy helps to predict clinical response and prognosis in multiple myeloma patients
Published in Hematology, 2023
Wuqiang Lin, Xiuli Chen, Heyong Zheng, Zhenjie Cai
It should be mentioned that there are two studies that explore the underlying mechanism of CDC37 in bortezomib resistance and multiple myeloma progression [15, 16], and they find that CDC37 inhibition facilitates bortezomib resistance and multiple myeloma progression, which seems to contradict with our results. However, one of these two studies has the same finding as us, they find that CDC37 is increased in newly diagnosed multiple myeloma patients compared to healthy individuals (they do not show this data in the results section, but mention this in the discussion section), which conflicts with their results of cell experiment [15]. The authors explain that the reason would be due to some subclones might already coexist within the tumor bulk at diagnosis. Bortezomib could serve as a selective pressure to eradicate the major subclones that are sensitive to bortezomib. While some minor subclones that are initially dormant and resistant to bortezomib would be survived. As a result, the key genes associated with bortezomib resistance are those diluted or quiescent ones [15]. Overall, CDC37 might be increased in the major subclones at diagnosis, and its lower expression is associated with bortezomib resistance. In our opinion, the two studies report that CDC37 suppression in the multiple myeloma cell line leads to bortezomib resistance via Xbp1s and autophagy [15, 16], while this procedure would be affected by the endogeneity of cells. Thus, the results of previous studies may lack the ability to reflect the role of CDC37 in vivo, and further experiments were required.
An updated patent review of anticancer Hsp90 inhibitors (2013-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Li Li, Nan-Nan Chen, Qi-Dong You, Xiao-Li Xu
Hsp90-dependent client proteins are correctly folded and matured through the Hsp90 chaperone cycle. Hsp90 chaperone cycle consists of three critical steps [15]: the conformational transformation of Hsp90 homodimer controlled by ATP/ADP binding; the formation of a super complex with co-chaperones; the release of matured client protein. Initially, Hsp90 homodimer exists in an open conformation with dimerization at the C-terminal domains. Unfolded client proteins, Hsp70 and the stress-inducible 1/Hsp70-Hsp90 organizing protein (HOP) form a ternary complex for Hsp90 binding[16]. The C-terminus of Hsp90 interacts with HOP, and the client proteins transfer to the M-terminal domain waiting for the closed status of Hsp90 N-terminus. The conformation varying is driven by ATP/ADP cycle[17]. The activity of ATPase is regulated by the activator of Hsp90 ATPase-1 (Aha1), which promotes ATP hydrolysis on the Hsp90 N-terminal pockets leading to the closure of Hsp90 N-terminus[18]. During this period, some co-chaperones such as Cdc37 binding to Hsp90 N-terminus partially impact the ATP-binding time. After that, ATP transfers to ADP, leading to the closure of Hsp90N, which provokes the maturation of clients. Meanwhile, p23 interacts with Hsp90N sequentially to form a super hetero-protein complex to stabilize the closed conformation. Then, client proteins fold into active stereostructure mediated by Hsp90 chaperone with ATP hydrolysis in Hsp90N. Hsp90-bound ADP caused the open conformation of Hsp90 N-terminal, resulted in the release of matured client proteins and the disassociation of co-chaperones. Then the restored Hsp90 chaperone enters into the next cycle for client proteins folding. The understanding of the Hsp90 chaperone cycle provides the molecular biology basis for the development of Hsp90 inhibitors[19].
Hydrogen deuterium exchange mass spectrometry applied to chaperones and chaperone-assisted protein folding
Published in Expert Review of Proteomics, 2019
Florian Georgescauld, Thomas E. Wales, John R. Engen
To understand the interaction between Hsp90 and client kinases, the group of J. Buchner used HDX MS to compare conformations of the non-client c-Src with several forms (v-Src, tail deletion mutant, multipoint mutation) that showed some dependence on Hsp90 [43]. There were significant changes in HDX in regions of suggested Hsp90 binding sites, supporting a model in which increased protein flexibility recruits Hsp90. Another study of Hsp90 and kinases involved the co-chaperone Cdc37 and aimed to characterize native destabilized mutants of B-RAF and FGFR3 kinases and the effects of binding to Cdc37 [44]. Cdc37 interactions with the substrate proteins caused destabilization of the N-lobe and partial stabilization of the C-lobe (Figure 5), but mostly in the mutant destabilized forms and not in the more stable wild-type kinase. The authors proposed that Cdc37: kinase complexes present a specific conformation that allows direct recognition by Hsp90. They also compared their HDX MS results for binary complexes to those of an earlier cryo-EM study [45] of a ternary complex with Cdc37, kinase and Hsp90 in which it was found that Hsp90 was responsible for separation of the N- and C-terminal lobes of the kinase. Their conclusions were that changes in the kinase in binary complexes (HDX MS, NMR, and CD) were not consistent with those of the cryo-EM structure of the ternary complex, suggesting that the ternary complex and Hsp90 perform additional changes to the kinase. This comparison makes the point that studies of larger, more complete multi-protein complexes that are closer to what may be found in vivo are more desirable than studies of only parts of a large complex. While such studies of large complexes by HDX MS are not currently routine, they are nonetheless possible, and are expected to become more commonplace in coming years.