Globally Approved EGFR Inhibitors: Insights into Their Syntheses, Target Kinases, Biological Activities, Receptor Interactions, and Metabolism

Molecules, Journal Year: 2021, Volume and Issue: 26(21), P. 6677 - 6677

Published: Nov. 4, 2021

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since FDA approval of first EGFR-TKI, erlotinib, great efforts have been devoted to discovery new potent inhibitors. Until now, fourteen globally approved for treatment different types cancers. Although these drugs showed high efficacy therapy, mutations emerged as big challenge drugs. In this review, we focus on that clinical uses These are classified based their chemical structures, target kinases, and pharmacological uses. The synthetic routes also discussed. crystal structures kinases summarized bonding modes interactions visualized. Based binding EGFR, into reversible irreversible cytotoxicity against cell lines summarized. addition, proposed metabolic pathways metabolites discussed, primary active reactive metabolites. Taken together, review highlights syntheses, interactions, cytotoxicity, metabolism data should greatly help design

Language: Английский

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Long non-coding RNA mediated drug resistance in breast cancer

Drug Resistance Updates, Journal Year: 2022, Volume and Issue: 63, P. 100851 - 100851

Published: July 1, 2022

Language: Английский

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Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: Focus on novel therapies

Lung Cancer, Journal Year: 2022, Volume and Issue: 170, P. 41 - 51

Published: May 21, 2022

Abstract

Tyrosine kinase inhibitors (TKIs) are the standard of care for patients with non-small cell lung cancer (NSCLC) that harbor mutations epidermal growth factor receptor (EGFR) gene. First-line therapy these is often osimertinib, a third-generation EGFR TKI. Erlotinib, gefitinib, afatinib, and dacomitinib first- second-generation TKIs also available. However, almost all eventually develop disease progression due to TKI-acquired resistance. The mechanisms resistance after TKI exposure involve or its downstream pathways. While frequently utilized strategy combating acquired remains platinum-based chemotherapy, clinical investigation promising novel agents targeting common such as MET, HER2, HER3 increased interest. In this review, we discuss in EGFR-mutant NSCLC, examine current treatment standards, developing therapies. Both EGFR-dependent (involving secondary EGFR) EGFR-independent (mutations bypass signaling histologic transformation) considered. Several strategies emerging overcome mechanisms, understanding identification specific EGFR-TKI continues improve. treatments development aim target resistance, including MET-, HER2-, HER3-directed molecular profiling at time initial may help identify relevant Clinical trial participation vital continued NSCLC.

Language: Английский

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Targeting cytokine and chemokine signaling pathways for cancer therapy

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: July 22, 2024

Abstract Cytokines are critical in regulating immune responses and cellular behavior, playing dual roles both normal physiology the pathology of diseases such as cancer. These molecules, including interleukins, interferons, tumor necrosis factors, chemokines, growth factors like TGF-β, VEGF, EGF, can promote or inhibit growth, influence microenvironment, impact efficacy cancer treatments. Recent advances targeting these pathways have shown promising therapeutic potential, offering new strategies to modulate system, progression, overcome resistance conventional therapies. In this review, we summarized current understanding implications cytokine chemokine signaling By exploring molecules biology response, highlighted development novel agents aimed at modulating combat The review elaborated on nature cytokines promoters suppressors tumorigenesis, depending context, discussed challenges opportunities presents for intervention. We also examined latest advancements targeted therapies, monoclonal antibodies, bispecific receptor inhibitors, fusion proteins, engineered variants, their metastasis, microenvironment. Additionally, evaluated potential combining therapies with other treatment modalities improve patient outcomes. Besides, focused ongoing research clinical trials that pivotal advancing our application cytokine- chemokine-targeted patients.

Language: Английский

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Toward the next generation EGFR inhibitors: an overview of osimertinib resistance mediated by EGFR mutations in non-small cell lung cancer

Cell Communication and Signaling, Journal Year: 2023, Volume and Issue: 21(1)

Published: April 11, 2023

Abstract Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is currently the standard first-line therapy for EGFR -mutated advanced non-small cell lung cancer (NSCLC). The life quality and survival of this subgroup patients were constantly improving owing to continuous iteration optimization EGFR-TKI. Osimertinib, an oral, third-generation, irreversible EGFR-TKI, was initially approved treatment NSCLC carrying T790M mutations, has become dominant targeted most mutant cancer. Unfortunately, resistance osimertinib inevitably develops during therefore limits its long-term effectiveness. For both fundamental clinical researchers, it stands a major challenge reveal mechanism, dire need develop novel therapeutics overcome resistance. In article, we focus on acquired caused by mutations which account approximately 1/3 all reported mechanisms. We also review proposed therapeutic strategies each type mutation conferring give outlook development next generation inhibitors.

Language: Английский

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Potentials and future perspectives of multi-target drugs in cancer treatment: the next generation anti-cancer agents

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: April 15, 2024

Abstract Cancer is a major public health problem worldwide with more than an estimated 19.3 million new cases in 2020. The occurrence rises dramatically age, and the overall risk accumulation combined tendency for cellular repair mechanisms to be less effective older individuals. Conventional cancer treatments, such as radiotherapy, surgery, chemotherapy, have been used decades combat cancer. However, emergence of novel fields research has led exploration innovative treatment approaches focused on immunotherapy, epigenetic therapy, targeted multi-omics, also multi-target therapy. hypothesis was based that drugs designed act against individual targets cannot usually battle multigenic diseases like Multi-target therapies, either combination or sequential order, recommended acquired intrinsic resistance anti-cancer treatments. Several studies multi-targeting treatments due their advantages include; overcoming clonal heterogeneity, lower multi-drug (MDR), decreased drug toxicity, thereby side effects. In this study, we'll discuss about drugs, benefits improving recent advances field multi-targeted drugs. Also, we will study performed clinical trials using therapeutic agents treatment.

Language: Английский

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HER2-targeted therapies in cancer: a systematic review

Biomarker Research, Journal Year: 2024, Volume and Issue: 12(1)

Published: Feb. 2, 2024

Abstract Abnormal alterations in human epidermal growth factor receptor 2 (HER2, neu, and erbB2) are associated with the development of many tumors. It is currently a crucial treatment for multiple cancers. Advanced molecular biology further exploration HER2-mediated pathway have promoted medicine design combination drug regimens. An increasing number HER2-targeted drugs including specific monoclonal antibodies, tyrosine kinase inhibitors (TKIs), antibody-drug conjugates (ADCs) been approved by U.S. Food Drug Administration. The emergence ADCs, has significantly transformed landscape various tumors, such as breast, gastric, bladder cancer. Classic antibodies novel TKIs not only demonstrated remarkable efficacy, but also expanded their indications, ADCs particular exhibiting profound clinical applications. Moreover concept low HER2 expression signifies breakthrough therapy, indicating that an tumors patients will benefit from this approach. This article, provides comprehensive review underlying mechanism action, representative drugs, corresponding trials, recent advancements, future research directions pertaining to therapy.

Language: Английский

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Triazoles in Medicinal Chemistry: Physicochemical Properties, Bioisosterism, and Application

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(10), P. 7788 - 7824

Published: May 3, 2024

Triazole demonstrates distinctive physicochemical properties, characterized by weak basicity, various dipole moments, and significant dual hydrogen bond acceptor donor capabilities. These features are poised to play a pivotal role in drug–target interactions. The inherent polarity of triazole contributes its lower logP, suggesting the potential improvement water solubility. metabolic stability adds additional value drug discovery. Moreover, metal-binding capacity nitrogen atom lone pair electrons has broad applications development metal chelators antifungal agents. This Perspective aims underscore unique attributes application. A comparative analysis involving isomers other heterocycles provides guiding insights for subsequent design triazoles, with hope offering valuable considerations designing medicinal chemistry.

Language: Английский

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Novel therapeutic agents in clinical trials: emerging approaches in cancer therapy

Discover Oncology, Journal Year: 2024, Volume and Issue: 15(1)

Published: Aug. 11, 2024

Novel therapeutic agents in clinical trials offer a paradigm shift the approach to battling this prevalent and destructive disease, area of cancer therapy is on precipice trans formative revolution. Despite importance tried-and-true treatments like surgery, radiation, chemotherapy, disease continues evolve adapt, making new, more potent methods necessary. The field currently witnessing emergence wide range innovative approaches. Immunotherapy, including checkpoint inhibitors, CAR-T cell treatment, vaccines, utilizes host's immune system selectively target eradicate malignant cells while minimizing harm normal tissue. development targeted medicines kinase inhibitors monoclonal antibodies has allowed for less harmful approaches treating cancer. With help genomics molecular profiling, "precision medicine" customizes therapies each patient's unique genetic makeup maximize efficacy unwanted side effects. Epigenetic therapies, metabolic interventions, radio-pharmaceuticals, an increasing emphasis combination with synergistic effects further broaden landscape. Multiple-stage are essential determining safety these novel drugs, allowing patients gain access also furthering scientific understanding. future rife promise, as integration artificial intelligence big data potential revolutionize early detection prevention. Collaboration among researchers, healthcare providers, active involvement remain bedrock ongoing battle against In conclusion, dynamic evolving landscape provides hope improved treatment outcomes, emphasizing patient-centered, data-driven, ethically grounded we collectively strive towards cancer-free world.

Language: Английский

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Phosphorylation-Dependent Regulation of WNT/Beta-Catenin Signaling

Frontiers in Oncology, Journal Year: 2022, Volume and Issue: 12

Published: March 14, 2022

WNT/β-catenin signaling is a highly complex pathway that plays diverse roles in various cellular processes. While WNT ligands usually signal through their dedicated Frizzled receptors, the decision to β-catenin-dependent or -independent manner rests upon type of co-receptors used. Canonical β-catenin-dependent, whereas non-canonical β-catenin-independent according classical definition. This still holds true, albeit with some added complexity, as both pathways seem cross-talk intertwined networks involve use different ligands, and co-receptors. β-catenin can be directly phosphorylated by kinases governing its participation either canonical pathways. Moreover, co-activators associate determine output terms induction genes promoting proliferation differentiation. In this review, we provide an overview how protein phosphorylation controls signaling, particularly human cancer.

Language: Английский

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