Following the design path of isoform-selective Hsp90 inhibitors: Small differences, great opportunities

Pharmacology & Therapeutics, Journal Year: 2023, Volume and Issue: 245, P. 108396 - 108396

Published: March 29, 2023

The heat shock protein 90 (Hsp90) family consists of four highly conserved isoforms: the mitochondrial TRAP-1, endoplasmic reticulum-localised Grp94, and cytoplasmic Hsp90α Hsp90β. Since late 1990s, this has been extensively studied as a potential target for treatment cancer, neurological disorders, infectious diseases. initial approach was to develop non-selective, so-called pan-Hsp90 ATP-competitive inhibitors N-terminal domain. Many these agents were tested in clinical trials, mainly but none them succeeded clinic. This due lack efficacy various toxicities associated with induction response (HSR). success prompted turn new approaches Hsp90 inhibition. Thus, selective particular isoform have developed. These isoform-selective do not induce HSR more targeted effect because all client proteins are equally dependent on paralogues Hsp90. However, it is extremely difficult such compounds conserved. Hsp90β an amazing 95% identity ATP binding site, differing only two amino acid residues. Therefore, focus review fully elucidate key structural features inhibitor classes terms site dissimilarities. In addition methodological characterisation structure-activity relationships, main advantages inhibition isoforms discussed.

Language: Английский

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Heat shock proteins as hallmarks of cancer: insights from molecular mechanisms to therapeutic strategies

Journal of Hematology & Oncology, Journal Year: 2024, Volume and Issue: 17(1)

Published: Sept. 4, 2024

Language: Английский

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Targeting HSP90 for Cancer Therapy: Current Progress and Emerging Prospects

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(18), P. 15968 - 15995

Published: Sept. 11, 2024

Heat shock protein 90 (HSP90), a highly conserved member of the heat family, regulates various proteins and signaling pathways involved in cancer, making it promising target for cancer therapy. Traditional HSP90 inhibitors have demonstrated significant antitumor potential preclinical trials, with over 20 compounds advancing to clinical trials showing results. However, limited efficacy shared toxicity these restrict their further use. Encouragingly, developing novel using conventional medicinal chemistry approaches─such as selective inhibitors, dual protein-protein interaction proteolysis-targeting chimeras─is expected address challenges. Notably, inhibitor TAS-116 has already been successfully marketed. In this Perspective, we summarize structure, biological functions, roles analyze status highlight latest advancements strategies, offering insights into future development.

Language: Английский

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Small-molecule dual inhibitors targeting heat shock protein 90 for cancer targeted therapy

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 139, P. 106721 - 106721

Published: July 8, 2023

Language: Английский

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New insight into the bioactivity of substituted benzimidazole derivatives: Repurposing from anti-HIV activity to cell migration inhibition targeting hnRNP M

Bioorganic & Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 86, P. 117294 - 117294

Published: April 26, 2023

Language: Английский

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Beyond Psychotropic: Repurposing of Fluoxetine Toward Cancer Management and Its Molecular Mechanisms

Published: Feb. 12, 2024

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed beneficial approach quick and cost-effective discovery process by skipping preclinical, Phase 1 trials pharmacokinetic studies. Several psychotropic drugs including selective serotonin reuptake inhibitors (SSRIs) tricyclic antide-pressants (TCAs) were studied their potential application in different diseases es-pecially cancer therapy. Fluoxetine (FLX) one of the most prescribed agents from SSRIs class treatment several neuropsychiatric disorders with favourable safety profile. FLX exhibited oncolytic effects via mechanisms dis-tinct its main serotonergic activity. Taking advantage ability to rapidly pen-etrate blood-brain barrier, could be particularly useful brain tumors. This was proved vitro vivo experiments using as monotherapy or combination temozolomide (TMZ) radiotherapy. In this review literature, we summarize pleiotropic roles against cancers highlighting multifaceted activities interrupt prolif-eration molecular even surmount multidrug resistance (MDR). We elaborated on successful synergistic combinations such FXR/temozolomide FXR/raloxifene glioblastoma breast cancer, respectively. showcased pharmaceutical load car-riers enhance efficacy cells. first article ex-tensively summarizing all previous repurposing studies management cancer.

Language: Английский

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Hiding in plain sight: Optimizing topoisomerase IIα inhibitors into Hsp90β selective binders

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 280, P. 116934 - 116934

Published: Oct. 5, 2024

Language: Английский

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Upgrade of chrysomycin A as a novel topoisomerase II inhibitor to curb KRAS-mutant lung adenocarcinoma progression

Pharmacological Research, Journal Year: 2022, Volume and Issue: 187, P. 106565 - 106565

Published: Nov. 19, 2022

A primary strategy employed in cancer therapy is the inhibition of topoisomerase II (Topo II), implicated cell survival. However, side effects and adverse reactions restrict utilization Topo inhibitors. Thus, investigations focus on discovery novel compounds that are capable inhibiting enzyme feature safer toxicological profiles. Herein, we upgrade an old antibiotic chrysomycin from Streptomyces sp. 891 as a compelling inhibitor. Our results show new chemical entity. Notably, targets DNA-unwinding with efficient binding potency significant intracellular levels. Intriguingly, kills KRAS-mutant lung adenocarcinoma cells negligible cytotoxic to normal at cellular level, thus indicating capability potential treatment. Furthermore, mechanism studies demonstrate inhibits stimulates accumulation reactive oxygen species, thereby inducing DNA damage-mediated apoptosis. Importantly, exhibits excellent control progression safety tumor-bearing models. provide scaffold for synthesis types inhibitors reveal target meet its further application.

Language: Английский

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First dual inhibitors of human topoisomerase IIα and Hsp90 C-terminal domain inhibit the growth of Ewing sarcoma in vitro and in vivo

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 153, P. 107850 - 107850

Published: Oct. 1, 2024

Language: Английский

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Beyond Psychotropic: Potential Repurposing of Fluoxetine toward Cancer Therapy

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(12), P. 6314 - 6314

Published: June 7, 2024

Drug repurposing, rebranding an existing drug for a new therapeutic indication, is deemed beneficial approach quick and cost-effective discovery process by skipping preclinical, Phase 1 trials pharmacokinetic studies. Several psychotropic drugs, including selective serotonin reuptake inhibitors (SSRIs) tricyclic antidepressants (TCAs), were studied their potential application in different diseases, especially cancer therapy. Fluoxetine (FLX) one of the most prescribed agents from SSRIs class treatment several neuropsychiatric disorders with favorable safety profile. FLX exhibited oncolytic effects via mechanisms distinct its main serotonergic activity. Taking advantage ability to rapidly penetrate blood-brain barrier, could be particularly useful brain tumors. This was proved vitro vivo experiments using as monotherapy or combination temozolomide (TMZ) radiotherapy. In this review literature, we summarize pleiotropic roles against cancers, highlighting multifaceted activities interrupt proliferation molecular even surmount multidrug resistance (MDR). We elaborated on successful synergistic combinations such FXR/temozolomide FXR/raloxifene glioblastoma breast cancer, respectively. showcased pharmaceutical load onto carriers enhance efficacy cells. first article extensively summarizing all previous repurposing studies management cancer.

Language: Английский

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