PROTAC’ing oncoproteins: targeted protein degradation for cancer therapy

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

Published: March 30, 2023

Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these is often related adaptive changes in target oncoprotein which reduce binding affinity. The arsenal therapies, moreover, lacks coverage several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality deplete protein by hijacking cellular destruction machinery. offer advantages therapy including resiliency acquired mutations protein, enhanced selectivity, lower dosing requirements, and potential abrogate oncogenic transcription factors scaffolding proteins. Herein, we review development proteolysis targeting chimeras (PROTACs) selected targets reported biological activities. medicinal chemistry PROTAC design has been area active research, but recent advances field will usher an era rational degrader design.

Language: Английский

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Heat Shock Response and Heat Shock Proteins: Current Understanding and Future Opportunities in Human Diseases

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(8), P. 4209 - 4209

Published: April 10, 2024

The heat shock response is an evolutionarily conserved mechanism that protects cells or organisms from the harmful effects of various stressors such as heat, chemicals toxins, UV radiation, and oxidizing agents. triggers expression a specific set genes proteins known genes/proteins molecular chaperones, including HSP100, HSP90, HSP70, HSP60, small HSPs. Heat (HSPs) play crucial role in thermotolerance aiding protecting insults stressors. HSPs are involved essential cellular functions protein folding, eliminating misfolded proteins, apoptosis, modulating cell signaling. stress to environmental has been extensively studied prokaryotes higher organisms. responses rely on intensity threshold stimuli, which vary among contexts. Studies have primarily focused HSPs, ubiquitin, along with their applications human biology. current review highlighted comprehensive explores function management, well potential therapeutic agents diagnostic markers for diseases.

Language: Английский

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The Vascular Endothelium and Coagulation: Homeostasis, Disease, and Treatment, with a Focus on the Von Willebrand Factor and Factors VIII and V

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(15), P. 8283 - 8283

Published: July 27, 2022

The vascular endothelium has several important functions, including hemostasis. homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins fibrinolytic antifibrinolytic ones. Coagulopathies are characterized by mutation-induced alteration the function certain coagulation factors or disturbed mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement nonreplacement treatments administration agents. Rebalancing products reestablish inhibiting natural pathways. These agents include monoclonal antibodies, such as concizumab marstacimab, which target tissue factor pathway inhibitor; interfering RNA therapies, fitusiran, targets antithrombin III; protease inhibitors, serpinPC, active protein C. In cases thrombophilia (deficiency C, S, V Leiden), treatment may direct oral anticoagulants, therapy (plasma recombinant ADAMTS13) congenital deficiency ADAMTS13, immunomodulators (prednisone) if autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) used context severe thrombophilia, regardless cause disorder. disseminated intravascular coagulation, choice consists antifibrinolytics, all-trans-retinoic acid, soluble human thrombomodulin.

Language: Английский

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The Beneficial and Adverse Effects of Autophagic Response to Caloric Restriction and Fasting

Advances in Nutrition, Journal Year: 2023, Volume and Issue: 14(5), P. 1211 - 1225

Published: July 30, 2023

Each cell is equipped with a conserved housekeeping mechanism, known as autophagy, to recycle exhausted materials and dispose of injured organelles via lysosomal degradation. Autophagy an early-stage cellular response stress stimuli in both physiological pathological situations. It thought that the promotion autophagy flux prevents host cells from subsequent injuries by removing damaged misfolded proteins. As correlate, modulation suggested therapeutic approach diverse conditions. Accumulated evidence suggests intermittent fasting or calorie restriction can lead induction adaptive increase longevity eukaryotic cells. However, prolonged excessive harmful stimulate type II autophagic death. Despite existence close relationship between deprivation different types, precise molecular mechanisms associated this phenomenon remain unclear. Here, we aimed highlight possible effects short-term on homeostasis.

Language: Английский

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Microalgae Produce Antioxidant Molecules with Potential Preventive Effects on Mitochondrial Functions and Skeletal Muscular Oxidative Stress

Antioxidants, Journal Year: 2023, Volume and Issue: 12(5), P. 1050 - 1050

Published: May 5, 2023

In recent years, microalgae have become a source of molecules for healthy life. Their composition carbohydrates, peptides, lipids, vitamins and carotenoids makes them promising new antioxidant molecules. Skeletal muscle is tissue that requires constant remodeling via protein turnover, its regular functioning consumes energy in the form adenosine triphosphate (ATP), which produced by mitochondria. Under conditions traumatic exercise or muscular diseases, high production reactive oxygen species (ROS) at origin oxidative stress (OS) will lead to inflammation atrophy, with life-long consequences. this review, we describe potential effects their biomolecules on mitochondrial functions skeletal during exercises musculoskeletal as sarcopenia, chronic obstructive pulmonary disease (COPD) Duchenne dystrophy (DMD), through increase regulation pathways synthesis.

Language: Английский

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Neuromodulatory effect of vardenafil on aluminium chloride/d-galactose induced Alzheimer’s disease in rats: emphasis on amyloid-beta, p-tau, PI3K/Akt/p53 pathway, endoplasmic reticulum stress, and cellular senescence

Inflammopharmacology, Journal Year: 2023, Volume and Issue: 31(5), P. 2653 - 2673

Published: July 17, 2023

Abstract Dysregulation of protein homeostasis, proteostasis, is a distinctive hallmark many neurodegenerative disorders and aging. Deleteriously, the accumulation aberrant proteins in Alzheimer’s disease (AD) accompanied with marked collapse proteostasis network. The current study explored potential therapeutic effect vardenafil (VAR), phosphodiesterase-5 inhibitor, AlCl 3 / d -galactose ( -gal)-induced AD rats its possible underlying mechanisms. impact VAR treatment on neurobehavioral function, hippocampal tissue architecture, activity cholinergic system main enzymes were assessed utilizing at doses 0.3 mg/kg 1 mg/kg. Additionally, expression level amyloid-beta phosphorylated tau hippocampus figured out. Accordingly, higher dose was selected to contemplate Intriguingly, elevated cyclic guanosine monophosphate averted repressed proteasome by -gal; hence, might alleviate burden toxic aggregates AD. In addition, substantial reduction activating transcription factor 6-mediated endoplasmic reticulum stress demonstrated treatment. Notably, counteracted -gal-induced depletion nuclear erythroid 2-related 2 level. Moreover, anti-senescence via ability restore balance redox circuit. modulation phosphatidylinositol-3-kinase/protein kinase B/p53 pathway kappa B level, key regulator senescence-associated secretory phenotype mediators release, also elucidated. Altogether, these findings insinuate benefits management. Graphic abstract

Language: Английский

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Hydrophobic tag-based protein degradation: Development, opportunity and challenge

European Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 260, P. 115741 - 115741

Published: Aug. 19, 2023

Language: Английский

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Targeting the Ubiquitin–Proteasome System and Recent Advances in Cancer Therapy

Cells, Journal Year: 2023, Volume and Issue: 13(1), P. 29 - 29

Published: Dec. 22, 2023

Ubiquitination is a reversible post-translational modification based on the chemical addition of ubiquitin to proteins with regulatory effects various signaling pathways. can alter molecular functions tagged substrates respect protein turnover, biological activity, subcellular localization or protein–protein interaction. As result, wide variety cellular processes are under ubiquitination-mediated control, contributing maintenance homeostasis. It follows that dysregulation ubiquitination reactions plays relevant role in pathogenic states human diseases such as neurodegenerative diseases, immune-related pathologies and cancer. In recent decades, enzymes ubiquitin–proteasome system (UPS), including E3 ligases deubiquitinases (DUBs), have attracted attention novel druggable targets for development new anticancer therapeutic approaches. This perspective article summarizes peculiarities shared by involved reaction which, when deregulated, lead tumorigenesis. Accordingly, an overview main pharmacological interventions targeting UPS clinical use still trials provided, also highlighting limitations efficacy these Therefore, attempts circumvent drug resistance side well UPS-related emerging technologies therapeutics discussed.

Language: Английский

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Small molecule agents for triple negative breast cancer: Current status and future prospects

Translational Oncology, Journal Year: 2024, Volume and Issue: 41, P. 101893 - 101893

Published: Jan. 29, 2024

Triple-negative breast cancer (TNBC) is a subtype of with poor prognosis. The number cases increased by 2.26 million in 2020, making it the most commonly diagnosed type world. TNBCs lack hormone receptor (HR) and human epidermal growth factor 2 (HER2), which limits treatment options. Currently, paclitaxel-based drugs combined other chemotherapeutics remain main for TNBC. There currently no consensus on best therapeutic regimen However, there have been successful clinical trials exploring large-molecule monoclonal antibodies, small-molecule targeted drugs, novel antibody-drug conjugate (ADC). Although antibodies produced success, their large molecular weight can limit benefits. It worth noting that past 30 years, FDA has approved small molecule HER2-positive cancers. effective targets occurrence drug resistance pose significant challenges To improve prognosis TNBC, crucial to search overcome resistance. This review examines efficacy, adverse effects, mechanisms, potential solutions both monotherapies combination therapies. New targets, including nuclear export protein 1 (XPO1) hedgehog (Hh), are emerging as options researchers become integrated into Additionally, growing interest degradation chimeras (PROTACs), degraders rogue proteins, future therapy direction. provides potentially valuable insights implications.

Language: Английский

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Role of protein degradation systems in colorectal cancer

Cell Death Discovery, Journal Year: 2024, Volume and Issue: 10(1)

Published: March 14, 2024

Abstract Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy–lysosome are the two primary pathways responsible directly related to cell survival. In malignant tumors, UPS plays a critical role in managing excessive load caused by cancer cells hyperproliferation. this review, we provide comprehensive overview of dual roles played autolysosome colorectal (CRC), elucidating their impact on initiation progression disease while also highlighting compensatory relationship. Simultaneously targeting both offers new promise enhancing treatment efficacy against CRC. Additionally, apoptosis closely linked ubiquitination autophagy, caspases degrade proteins. A thorough comprehension interplay between various highly important clarifying mechanism underlying onset

Language: Английский

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