Overcoming cancer therapy resistance: From drug innovation to therapeutics

Drug Resistance Updates, Год журнала: 2025, Номер 81, С. 101229 - 101229

Опубликована: Март 8, 2025

Язык: Английский

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Targeting Extracellular Signal-Regulated Protein Kinase 1/2 (ERK1/2) in Cancer: An Update on Pharmacological Small-Molecule Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2022, Номер 65(20), С. 13561 - 13573

Опубликована: Окт. 7, 2022

Extracellular signal-regulated protein kinase 1/2 (ERK1/2), the only known substrate of MEK1/2, is located downstream RAS-RAF-MEK-ERK (MAPK) pathway and associated with abnormal activation poor prognosis cancer. To date, several small-molecule inhibitors RAS, RAF, MEK have been reported to make rapid advances in cancer therapy; however, acquired resistance still occurs, thereby weakening therapeutic efficacy these inhibitors. Recently, selective inhibition ERK1/2 has regarded as a potential strategy that can not effectively block MAPK but also overcome drug caused by upstream mutations MEK. Herein, we summarize oncogenic roles, key signaling network, single- dual-target preclinical clinical trials. Together, inspiring findings shed new light on discovery more candidate drugs improve therapeutics.

Язык: Английский

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Development and therapeutic potential of adaptor-associated kinase 1 inhibitors in human multifaceted diseases

European Journal of Medicinal Chemistry, Год журнала: 2023, Номер 248, С. 115102 - 115102

Опубликована: Янв. 7, 2023

Язык: Английский

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Anticancer and anti-inflammatory effects of novel ethyl pyrazole derivatives having sulfonamide terminal moiety

Bioorganic Chemistry, Год журнала: 2024, Номер 153, С. 107825 - 107825

Опубликована: Сен. 16, 2024

Язык: Английский

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Computational Development of Allosteric Peptide Inhibitors Targeting LIM Kinases as a Novel Therapeutic Intervention

Cell Biochemistry and Biophysics, Год журнала: 2025, Номер unknown

Опубликована: Март 18, 2025

Язык: Английский

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Profiling of small‐molecule necroptosis inhibitors based on the subpockets of kinase–ligand interactions

Medicinal Research Reviews, Год журнала: 2023, Номер 43(6), С. 1974 - 2024

Опубликована: Апрель 29, 2023

Abstract Necroptosis is a highly regulated cell death (RCD) form in various inflammatory diseases. Receptor‐interacting protein kinase 1 (RIPK1) and RIPK3 are involved the pathway. Targeting domains of RIPK1 and/or 3 drug design strategy for related It generally accepted that essential reoccurring features observed across human domains, including RIPK3. They present common N‐ C‐terminal built up mostly by α‐helices β‐sheets, respectively. The current RIPK1/3 inhibitors mainly interact with catalytic cleft. This article aims to an in‐depth profiling ligand–kinase interactions crucial cleft areas carefully aligning kinase‐ligand cocrystal complexes or molecular docking models. similarity differential structural segments ligands systematically evaluated. New insights on adaption conserved selective diversity chemical scaffolds also provided. In word, our analysis can provide better requirement inhibition guide inhibitor discovery optimization their potency selectivity.

Язык: Английский

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Insights into the post-translational modifications in heart failure

Ageing Research Reviews, Год журнала: 2024, Номер 100, С. 102467 - 102467

Опубликована: Авг. 25, 2024

Язык: Английский

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Isoform-selective targeting of PI3K: time to consider new opportunities?

Trends in Pharmacological Sciences, Год журнала: 2023, Номер 44(9), С. 601 - 621

Опубликована: Июль 11, 2023

Язык: Английский

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Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

ACS Chemical Biology, Год журнала: 2023, Номер 18(10), С. 2101 - 2113

Опубликована: Июнь 29, 2023

Ribonucleases (RNases) cleave and process RNAs, thereby regulating the biogenesis, metabolism, degradation of coding noncoding RNAs. Thus, small molecules targeting RNases have potential to perturb RNA biology, been studied as therapeutic targets antibiotics, antivirals, agents for autoimmune diseases cancers. Additionally, recent advances in chemically induced proximity approaches led discovery bifunctional that target achieve or inhibit processing. Here, we summarize efforts made discover small-molecule inhibitors activators bacterial, viral, human RNases. We also highlight emerging examples RNase-targeting discuss trends developing such both biological applications.

Язык: Английский

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Tilting the Scales toward EGFR Mutant Selectivity: Expanding the Scope of Bivalent “Type V” Kinase Inhibitors

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(23), С. 21438 - 21469

Опубликована: Дек. 3, 2024

Binding multiple sites within proteins with bivalent compounds is a strategy for developing uniquely active agents. A new class of dual-site inhibitors has emerged targeting the epidermal growth factor receptor (EGFR) anchored to both orthosteric (ATP) and allosteric sites. Despite proof-of-concept successes, enabling selectivity against oncogenic activating mutations not been achieved classifying these among kinase remains underexplored. This study investigates structure–activity relationships, binding modes, biological activity ATP-allosteric (AABIs). We find that AABIs selectively inhibit drug-resistant EGFR mutants (L858R/T790M L858R/T790M/C797S) by anchoring methyl isoindolinone moiety along αC-helix channel site. In contrast, related Type I1/2 target wild-type but are less effective resistant mutants. shift in demonstrates mutant-selective classify as "Type V" inhibitors.

Язык: Английский

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