Review
Chemistry, Medicinal
Lei Wang, Qiuyue Zhang, Qidong You
Summary: Heat shock protein 90 (HSP90) is crucial in cancer cells, but its inhibitors have limited efficacy and side effects. Researchers are investigating the disruption of the HSP90-CDC37-kinase complex as an alternative solution to avoid limitations.
MEDICINAL RESEARCH REVIEWS
(2022)
Article
Biochemistry & Molecular Biology
Sara Garcia-Alonso, Pablo Mesa, Laura de la Puente Ovejero, Gonzalo Aizpurua, Carmen G. Lechuga, Eduardo Zarzuela, Clara M. Santiveri, Manuel Sanclemente, Javier Munoz, Monica Musteanu, Ramon Campos-Olivas, Jorge Martinez-Torrecuadrada, Mariano Barbacid, Guillermo Montoya
Summary: This study describes the structure of the RAF1 protein in complex with HSP90 and CDC37. The research reveals that CDC37 can differentiate between different members of the RAF family. Additionally, the study shows that folded RAF1 assembles with 14-3-3 dimers, and disrupting the interaction between CDC37 and RAF1 may have potential therapeutic implications.
Article
Biochemistry & Molecular Biology
Sarah Kowallik, Andreas Kritikos, Matthias Kaestle, Christoph Thurm, Burkhart Schraven, Luca Simeoni
Summary: Experimental data does not support the idea that Cdc37 regulates the activity/stability of Lck, as evidenced by unaffected Lck stability and TCR signaling in T cells with augmented or suppressed Cdc37 expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Dennis M. Bjorklund, R. Marc L. Morgan, Jasmeen Oberoi, Katie L. I. M. Day, Panagiota A. Galliou, Chrisostomos Prodromou
Summary: The study identified the interaction between CDC37 and BRAF and determined the crucial structural elements of CDC37 involved in BRAF recognition. The dimerization of BRAF can inhibit the recognition by CDC37, and the consequences of BRAF mutations on signaling were discussed.
Article
Biochemistry & Molecular Biology
Yoshihiko Miyata, Eisuke Nishida
Summary: The DYRK family comprises five related protein kinases, with DYRK1A linked to disorders such as Down syndrome. It was found that Hsp90 and Cdc37 are specific cellular protein chaperones for DYRK1B and DYRK4, playing a crucial role in quality control of these kinases.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
(2021)
Article
Multidisciplinary Sciences
Dimitra Keramisanou, M. V. Vasantha Kumar, Nicole Boose, Rinat R. Abzalimov, Ioannis Gelis
Summary: This study investigates the recruitment and loading mechanism of protein kinases to the Hsp90-Cdc37 complex, which is the first step in Hsp90-mediated chaperoning. The results show that the conformational dynamics of all partners are critical for the loading mechanism, and that Cdc37 plays a role in sensing clients by stabilizing the preexisting partially unfolded client state. These findings reveal the regulatory mechanism of molecular chaperones in maintaining protein homeostasis.
Article
Chemistry, Multidisciplinary
Chuan-jing Cheng, Kai-xin Liu, Man Zhang, Fu-kui Shen, Li-li Ye, Wen-bo Wu, Xiao-tao Hou, Er-wei Hao, Yuan-yuan Hou, Gang Bai
Summary: This study identified a novel natural inhibitor of HSP90, okicamelliaside (OCS), which selectively inhibits the formation of the HSP90-CDC37 protein complex and disrupts protein-protein interactions of HSP90-CDC37 to exert anti-tumor effects.
ACTA PHARMACOLOGICA SINICA
(2022)
Article
Chemistry, Medicinal
Qiuyue Zhang, Xuexuan Wu, Jianrui Zhou, Lixiao Zhang, Xiaoli Xu, Lianshan Zhang, Qidong You, Lei Wang
Summary: The HSP90-CDC37 protein-protein interaction system is crucial for kinase maturation and targeting this interaction has emerged as a promising strategy for cancer therapy. By studying inhibitors, a key hydrophobic pocket was identified, leading to the design of an optimum compound DDO-5994 with improved binding affinity and antiproliferative activity.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Na Li, Manyi Xu, Lulu Zhang, Zhichao Lei, Cheng Chen, Tianyuan Zhang, Li Chen, Jianbo Sun
Summary: By introducing substituted imidazoles, significant improvements in antiproliferation, covalent-binding ability, and Hsp90-Cdc37 inhibition were achieved compared to CEL. Compound 9, the most potent derivative, showed higher activity in inducing apoptosis and inhibiting tumor growth in vivo. This study provides support for the development of CEL and other Michael acceptors as antitumor agents.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Biochemistry & Molecular Biology
Chrisostomos Prodromou, Dennis M. Bjorklund
Summary: Hsp90, an ATP molecular chaperone, plays a crucial role in the activation and maturation of client proteins. Recent studies have shed light on the mechanism of Hsp90, including its ATP hydrolysis and the remodeling of client proteins for their activation.
Article
Multidisciplinary Sciences
Maximilian M. Biebl, Abraham Lopez, Alexandra Rehn, Lee Freiburger, Jannis Lawatscheck, Birgit Blank, Michael Sattler, Johannes Buchner
Summary: The study shows that a tryptophan residue in the proximal region of the p23 tail decelerates the ATPase of Hsp90 by altering the conformation of the catalytic loop, while a conserved helical motif in the p23 tail interacts with the client protein binding site of Hsp90 and is involved in the activation of the client protein in the cellular context.
NATURE COMMUNICATIONS
(2021)
Review
Biochemistry & Molecular Biology
Anna G. Mankovich, Brian C. Freeman
Summary: Heat shock protein 90 (Hsp90), a highly conserved molecular chaperone, not only maintains the stability of metastable proteins, but also plays a crucial role in protein transport. The specific contributions of Hsp90 to protein transport are still not well defined, despite numerous connections with factors involved in this process.
Editorial Material
Pharmacology & Pharmacy
Marco P. Licciardello, Paul Workman
Summary: Casein kinase 2, a potential therapeutic target in cancer due to its high expression, did not exhibit broad antiproliferative activity in cancer cells when targeted by the new inhibitor SGC-CK2-1, developed by Wells and colleagues.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2021)
Article
Biochemistry & Molecular Biology
Prajakta Prakash Dike, Shovonlal Bhowmick, Gaber E. Eldesoky, Saikh M. Wabaidur, Preeti Chunarkar Patil, Md Ataul Islam
Summary: Protein-protein interactions play a crucial role in cellular processes and dysregulation can lead to various diseases including cancer. Targeting intracellular protein-protein interactions is important for cancer therapy. In this study, a set of compounds were screened for their ability to inhibit the Hsp90-Cdc37 interaction, which is an important target for cancer therapeutic development. Four molecules were identified and further evaluated using pharmacokinetics parameters, pharmacophore analyses, and molecular dynamics simulation, confirming their potential for inhibiting the Hsp90-Cdc37 interface.
JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
(2022)
Article
Biochemistry & Molecular Biology
Vanessa Nguyen, Ethan Ahler, Katherine A. Sitko, Jason J. Stephany, Dustin J. Maly, Douglas M. Fowler
Summary: Hsp90 is a molecular chaperone involved in the refolding and activation of protein substrates. By studying a large number of variants, we identified functionally dependent client variants of the Src kinase and identified the factors driving Hsp90 dependence.