Unveiling the HSF1 Interaction Network: Key Regulators of Its Function in Cancer DOI Open Access

Snezhana A. Vladimirova,

Nadezhda E. Kokoreva, Irina V. Guzhova

и другие.

Cancers, Год журнала: 2024, Номер 16(23), С. 4030 - 4030

Опубликована: Ноя. 30, 2024

Heat shock factor 1 (HSF1) plays a central role in orchestrating the heat response (HSR), leading to activation of multiple proteins (HSPs) genes and approximately thousands other involved various cellular functions. In cancer cells, HSPs play particular coping with accumulation damaged resulting from dysregulated translation post-translational processes. This proteotoxic stress is hallmark cells causes constitutive HSR. Beyond its HSR, HSF1 regulates diverse processes critical for tumor including proliferation, cell death, drug resistance. Emerging evidence also highlights HSF1's involvement remodeling immune microenvironment as well maintenance stem cells. Consequently, has emerged an attractive therapeutic target, prompting development specific inhibitors that have progressed clinical trials. Importantly, possesses broad interactome, forming protein-protein interactions (PPIs) components signaling pathways, transcription factors, chromatin regulators. Many these interactors modulate activity HSF1-dependent gene expression are well-recognized targets therapy. review summarizes current knowledge on molecular chaperones, protein kinases, regulatory proteins. Understanding key promoting progression, along identifying factors disrupt complexes, may offer valuable insights developing innovative strategies against cancer.

Язык: Английский

Synthesis, Anticancer Screening, and In Silico Evaluations of Thieno[2,3-c]pyridine Derivatives as Hsp90 Inhibitors DOI Creative Commons
Balakumar Chandrasekaran, Mohammad F. Bayan, Ali Hmedat

и другие.

Pharmaceuticals, Год журнала: 2025, Номер 18(2), С. 153 - 153

Опубликована: Янв. 24, 2025

Background: Thieno[2,3-c]pyridines and their analogs are not well explored for anticancer properties. Hence, our research aimed to establish the potential of thieno[2,3-c]pyridines through cell-based assays in silico evaluations. Methods: Thieno[2,3-c]pyridine derivatives 6(a–k) were synthesized characterized using FT-IR, 1H-NMR, 13C-NMR, HRMS. All compounds screened initially activity against MCF7 T47D (breast cancer), HSC3 (head neck RKO (colorectal cancer) cell lines MTT assay. Apoptosis cycle analyses conducted Annexin V/propidium iodide (PI) double staining apoptosis assessment PI analysis investigate mechanisms underlying reduced viability. In molecular docking was accomplished Hsp90 determined pharmacokinetics Results: From screening assay, 6a 6i identified as inhibitors further subjected IC50 determination. The compound showed potent inhibition (IC50 = 10.8 µM), 11.7 12.4 µM) lines, all which indicated a broad spectrum activity. Notably, found induce G2 phase arrest, thereby inhibiting progression. Molecular results crucial interactions ligands target Hsp90. Conclusion: induced death via that different from apoptosis. Thus, thieno[2,3-c]pyridine can be suitable lead optimized obtain agents inhibition.

Язык: Английский

Процитировано

1
Advances in the structures, mechanisms and targeting of molecular chaperones DOI Creative Commons

Jinying Gu,

Yanyi He, Chenxi He

и другие.

Signal Transduction and Targeted Therapy, Год журнала: 2025, Номер 10(1)

Опубликована: Март 12, 2025

Abstract Molecular chaperones, a class of complex client regulatory systems, play significant roles in the prevention protein misfolding and abnormal aggregation, modulation homeostasis, protection cells from damage under constantly changing environmental conditions. As understanding biological mechanisms molecular chaperones has increased, their link with occurrence progression disease suggested that these proteins are promising targets for therapeutic intervention, drawing intensive interest. Here, we review recent advances determining structures heat shock 90 (HSP90) chaperone system complexes. We also describe features shed light on complicated mechanism operates through interactions various co-chaperones cycles. In addition, how affect diseases by regulating pathogenic been thoroughly analyzed. Furthermore, focus to systematically discuss clinical drug design strategies preclinical stage. Recent studies have identified variety novel targeting systems compounds act different those traditional inhibitors. Therefore, as more developed, will significantly contribute discovery new potential drugs.

Язык: Английский

Процитировано

1
The structural and functional dynamics of BiP and Grp94: opportunities for therapeutic discovery DOI
Ikponwmosa Obaseki,

Chioma C Ndolo,

Ayodeji Adeola Adedeji

и другие.

Trends in Pharmacological Sciences, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

1
Identification of a New Pentafluorosulfanyl-Substituted Chalcone with Activity Against Hepatoma and Human Parasites DOI Creative Commons

Alessandra Viperino,

Michael Höpfner,

Nicole Edel

и другие.

Pharmaceuticals, Год журнала: 2025, Номер 18(1), С. 50 - 50

Опубликована: Янв. 3, 2025

Background/Objectives: New drugs are required for the treatment of liver cancers and protozoal parasite infections. Analogs known anticancer active antileishmanial 2′,4′,6′-trimethoxychalcone SU086 were prepared investigated. Methods: The chalcones according to Claisen–Schmidt condensation protocol analyzed. They tested activity against two cancer cell lines (HepG2 HuH-7) parasites (Toxoplasma gondii Leishmania major). Unspecific toxicity expression Hsp90 Hsp70 upon analyzed in cells. Results: A new chalcone, 2′,4′,6′-trimethoxy-3-pentafluorosulfanylchalcone (246TMP-3SF5), with a pentafluorosulfanyl (SF5) substituent showed pronounced activities cells T. which superior parent chalcone these models. In contrast, its anthracene analog 2′,4′,6′-trimethoxy-9-anthracenylchalcone (246TMP-Anth) most L. major promastigotes. SF5-substituted behaved like inhibitor 17-AAG upregulated Conclusions: has potential become drug therapy hepatoma toxoplasmosis.

Язык: Английский

Процитировано

0
Assessment of Hsp90β-selective inhibitor safety and on-target effects DOI Creative Commons

Tyelor S. Reynolds,

Sanket Mishra, Brian S. J. Blagg

и другие.

Scientific Reports, Год журнала: 2025, Номер 15(1)

Опубликована: Янв. 29, 2025

The heat shock protein 90 (Hsp90) family of molecular chaperones mediates the folding and activation ~ 400 client proteins, many which contribute to oncogenesis. As a result, Hsp90 pan-inhibitors, inhibit all four isoforms, have been investigated in clinic for treatment cancer. Unfortunately, detrimental side effects were observed hindered clinical development pan-Hsp90 inhibitors. two most common on-target toxicities, cardio-toxicity ocular-toxicity, attributed inhibition Hsp90α isoform. an alternative strategy, Hsp90β-selective inhibitors developed, shown promising anti-cancer activity vitro vivo combination with immune-checkpoint blockade therapy. This study aims assess potential risks ocular-toxicity exhibited by vitro. In summary, NDNB1182 was found avoid cardio- typical pan-inhibitors (e.g. 17-AAG), providing path toward generation isoform-selective

Язык: Английский

Процитировано

0
The possibilities and challenges associated with selective targeting Plasmodium falciparum Hsp90 for malaria DOI

Thato Matlhodi,

Lisema Patrick Makatsela,

Njabulo Joyfull Gumede

и другие.

Transactions of the Royal Society of South Africa, Год журнала: 2025, Номер unknown, С. 1 - 18

Опубликована: Фев. 7, 2025

Язык: Английский

Процитировано

0
A Comprehensive Overview of Protacs Targeting Hsp90 and Their Client Proteins for Cancer Therapy DOI
Gulshan Kumar,

Gouri Tyagi,

Vikramdeep Monga

и другие.

Опубликована: Янв. 1, 2025

Язык: Английский

Процитировано

0
Lung cancer associated transcript 1 binds heat shock protein 90 to promote growth of hepatocellular carcinoma DOI Creative Commons

Yi Bai,

Haohai Zhang,

Zijie Lin

и другие.

Cellular Signalling, Год журнала: 2025, Номер 129, С. 111671 - 111671

Опубликована: Фев. 17, 2025

Язык: Английский

Процитировано

0
Mechanisms and applications of mitochondrial chaperone inhibitors DOI
Gianna Mochi, Mark R. Woodford

Transactions of the Royal Society of South Africa, Год журнала: 2025, Номер unknown, С. 1 - 10

Опубликована: Фев. 25, 2025

Язык: Английский

Процитировано

0
In Silico Identification of Spirodioxynaphthalenes as Promising Hsp90 Inhibitors DOI Creative Commons
Adam A. Aboalroub

Research Square (Research Square), Год журнала: 2025, Номер unknown

Опубликована: Март 12, 2025

Abstract The ATPase activity of Hsp90 is critical for cancer progression, as it maintains the stability oncogenic proteins, thereby supporting tumor cell survival. Although small-molecule inhibitors targeting this have shown preclinical promise, toxicity and insufficient efficacy hindered their progress in clinical trials. Accordingly, expanding search novel remains paramount. Spirodioxynaphthalenes, a rapidly class fungal secondary metabolites, exhibit remarkable breadth bioactive properties, including antitumor, antibacterial, antifungal, enzymatic inhibitory activities. This study employed an in-silico methodology to identify spirodioxynaphthalene derivatives potential Hsp90’s activity. We identified thirteen spirodioxynaphthalenes from natural product databases These compounds, with favorable drug-like promising predicted pharmacokinetics cytotoxicity, potent binding energies ranging − 10.016 -10.636 kcal/mol, emerge compelling candidates further optimization. Their interactions, which reveal key hydrogen bonds hydrophobic interactions catalytic residues Lys58, Gly97, Thr184, bolster inhibitors. findings firmly suggest that could represent chemotype developing Hsp90-targeted therapeutics, providing ray hope future treatment. Further mechanistic validation development are necessary advance these compounds towards application.

Язык: Английский

Процитировано

0