Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies

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

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

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Targeting the tumor stroma for cancer therapy

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Nov. 2, 2022

Tumors are comprised of both cancer cells and surrounding stromal components. As an essential part the tumor microenvironment, stroma is highly dynamic, heterogeneous commonly tumor-type specific, it mainly includes noncellular compositions such as extracellular matrix unique cancer-associated vascular system well a wide variety cellular components including activated fibroblasts, mesenchymal cells, pericytes. All these elements operate with each other in coordinated fashion collectively promote initiation, progression, metastasis therapeutic resistance. Over past few decades, numerous studies have been conducted to study interaction crosstalk between neoplastic cells. Meanwhile, we also witnessed exponential increase investigation recognition critical roles solid tumors. A series clinical trials targeting launched continually. In this review, introduce discuss current advances understanding various their cancers. We elaborate on potential novel approaches for tumor-stroma-based targeting, aim leap from bench bedside.

Language: Английский

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Pan-cancer spatially resolved single-cell analysis reveals the crosstalk between cancer-associated fibroblasts and tumor microenvironment

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: Oct. 13, 2023

Cancer-associated fibroblasts (CAFs) are a heterogeneous cell population that plays crucial role in remodeling the tumor microenvironment (TME). Here, through integrated analysis of spatial and single-cell transcriptomics data across six common cancer types, we identified four distinct functional subgroups CAFs described their distribution characteristics. Additionally, RNA sequencing (scRNA-seq) from three additional types two newly generated scRNA-seq datasets rare namely epithelial-myoepithelial carcinoma (EMC) mucoepidermoid (MEC), expanded our understanding CAF heterogeneity. Cell-cell interaction conducted within context highlighted pivotal roles matrix (mCAFs) angiogenesis inflammatory (iCAFs) shaping immunosuppressive microenvironment. In patients with breast (BRCA) undergoing anti-PD-1 immunotherapy, iCAFs demonstrated heightened capacity facilitating proliferation, promoting epithelial-mesenchymal transition (EMT), contributing to establishment an Furthermore, scoring system based on showed significant correlation immune therapy response melanoma patients. Lastly, provided web interface ( https://chenxisd.shinyapps.io/pancaf/ ) for research community investigate pan-cancer.

Language: Английский

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Recent development of multi-target VEGFR-2 inhibitors for the cancer therapy

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 133, P. 106425 - 106425

Published: Feb. 15, 2023

Language: Английский

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Cancer cells co-opt nociceptive nerves to thrive in nutrient-poor environments and upon nutrient-starvation therapies

Cell Metabolism, Journal Year: 2022, Volume and Issue: 34(12), P. 1999 - 2017.e10

Published: Nov. 16, 2022

Language: Английский

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Recent development of VEGFR small molecule inhibitors as anticancer agents: A patent review (2021–2023)

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 146, P. 107278 - 107278

Published: March 9, 2024

Language: Английский

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Hyperthermia in Combination with Emerging Targeted and Immunotherapies as a New Approach in Cancer Treatment

Cancers, Journal Year: 2024, Volume and Issue: 16(3), P. 505 - 505

Published: Jan. 24, 2024

Despite significant advancements in the development of novel therapies, cancer continues to stand as a prominent global cause death. In many cases, cornerstone standard-of-care therapy consists chemotherapy (CT), radiotherapy (RT), or combination both. Notably, hyperthermia (HT), which has been clinical use last four decades, proven enhance effectiveness CT and RT, owing its recognized potency sensitizer. Furthermore, HT exerts effects on all steps cancer–immunity cycle impact key oncogenic pathways. Most recently, there noticeable expansion research related treatment options involving immunotherapy (IT) targeted (TT), trend also visible pipelines pharmaceutical companies. However, potential results arising from these innovative therapeutic approaches with remain largely unexplored. Therefore, this review aims explore oncology major companies, primary objective identifying principal targets forthcoming therapies that have be advantageous for patients by specifically targeting molecular pathways involved HT. The ultimate goal is pave way future initiatives trials harness synergy between emerging IT TT medications when used conjunction

Language: Английский

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Nanostructured lipid carriers (NLCs): A promising candidate for lung cancer targeting

International Journal of Pharmaceutics, Journal Year: 2024, Volume and Issue: 655, P. 123986 - 123986

Published: March 15, 2024

Language: Английский

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The VEGFs/VEGFRs system in Alzheimer’s and Parkinson’s diseases: Pathophysiological roles and therapeutic implications

Pharmacological Research, Journal Year: 2024, Volume and Issue: 201, P. 107101 - 107101

Published: Feb. 7, 2024

The vascular endothelial growth factors (VEGFs) and their cognate receptors (VEGFRs), besides well-known involvement in physiological angiogenesis/lymphangiogenesis diseases associated to pathological vessel formation, play multifaceted functions the central nervous system (CNS). In addition shaping brain development, by controlling cerebral vasculogenesis regulating neurogenesis as well astrocyte differentiation, VEGFs/VEGFRs axis exerts essential adult both contexts. this article, after describing CNS, we focus on neurodegenerative reviewing current literature rather complex contribution pathogenic mechanisms of Alzheimer's (AD) Parkinson's (PD) diseases. Thereafter, based outcome targeting animal models AD PD, discuss factual relevance pharmacological modulation a novel potential disease-modifying approach for these pathologies. Specific VEGFRs targeting, aimed at selective VEGFR-1 inhibition, while preserving VEGFR-2 signal transduction, appears promising strategy hit molecular underlying pathology. Moreover, therapeutic VEGFs-based approaches can be proposed PD treatment, with aim fine-tuning levels amplify neurotrophic/neuroprotective effects limiting an excessive impact permeability.

Language: Английский

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Pyrimidine scaffold dual‐target kinase inhibitors for cancer diseases: A review on design strategies, synthetic approaches, and structure–activity relationship (2018‒2023)

Archiv der Pharmazie, Journal Year: 2025, Volume and Issue: 358(1)

Published: Jan. 1, 2025

Abstract Cancer, the second leading cause of death globally, causes a significant threat to life. Despite advancements in treatment cancer, persistent challenges include severe side effects and emergence acquired drug resistance. Additionally, many traditional chemotherapy drugs show restricted efficacy high toxicity, primarily attributed their lack selectivity. Thus, development targeting protein kinases has emerged as noteworthy priority for addressing human cancers. Medicinal chemists have shown considerable interest dual candidates strategy create medicines that are safer, more efficient, cost‐effective. Furthermore, Food Drug Administration (FDA) approved several dual‐target anticancer treatment, emphasizing lower risks interactions improved pharmacokinetics safety profiles. This review focuses on synthetic efforts, design strategies, structure–activity relationship pyrimidine scaffold‐based kinase inhibitors developed with potential within recent 6 years (2018‒2023). Collectively, these strategies expected offer fresh perspectives future directions pyrimidine‐based design, potentially advancing cancer therapeutics.

Language: Английский

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