MDM2 Inhibitors for Cancer Therapy: The Past, Present, and Future

Pharmacological Reviews, Journal Year: 2024, Volume and Issue: 76(3), P. 414 - 453

Published: March 15, 2024

Since its discovery over 35 years ago, MDM2 has emerged as an attractive target for the development of cancer therapy. MDM29s activities extend from carcinogenesis to immunity, response various therapies. report first inhibitor more than 30 approaches inhibit have been attempted, with hundreds small molecule inhibitors evaluated in preclinical studies and numerous molecules tested clinical trials. Although many degraders trials, there is currently no FDA-approved on market. Nevertheless, are several current trials promising agents that may overcome past failures, including granted FDA orphan drug or fast-track status. We herein summarize research efforts discover develop inhibitors, focusing those induce degradation exert anticancer activity, regardless p53 status cancer. also describe how investigations moved towards combining other agents, immune checkpoint inhibitors. Finally, we discuss challenges future directions accelerate application In conclusion, targeting remains a treatment approach, protein represents novel strategy downregulate without side effects existing blocking p53-MDM2 binding. Additional needed finally realize full potential inhibition treating chronic diseases where implicated. Significance Statement Overexpression/amplification oncogene detected human cancers associated disease progression, resistance, poor patient outcomes. Herein, review previous, emerging MDM2-targeted therapies chemotherapy immunotherapy regimens. The findings these contemporary lead safer effective treatments patients overexpressing MDM2.

Language: Английский

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Advances in nucleic acid-based cancer vaccines

Journal of Biomedical Science, Journal Year: 2025, Volume and Issue: 32(1)

Published: Jan. 21, 2025

Abstract Nucleic acid vaccines have emerged as crucial advancements in vaccine technology, particularly highlighted by the global response to COVID-19 pandemic. The widespread administration of mRNA against billions globally marks a significant milestone. Furthermore, approval an for Respiratory Syncytial Virus (RSV) this year underscores versatility technology. In oncology, combination encoding neoantigens and immune checkpoint inhibitors (ICIs) has shown remarkable efficacy eliciting protective responses diseases like melanoma pancreatic cancer. Although use DNA been limited India, inherent stability at room temperature cost-effectiveness present viable option that could benefit developing countries. These advantages may help address some challenges associated with vaccines. Currently, several trials are exploring DNA-encoded ICIs across various cancer types. studies highlight promising role nucleic acid-based next generation immunotherapeutic agents treatment. This review will delve into recent current developmental status both DNA-based

Language: Английский

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Exploiting the Specificity of CRISPR/Cas System for Nucleic Acids Amplification-Free Disease Diagnostics in the Point-of-Care

Chem & Bio Engineering, Journal Year: 2024, Volume and Issue: 1(4), P. 330 - 339

Published: Jan. 9, 2024

Rapid and reliable molecular diagnostics employing target nucleic acids small biomarkers are crucial strategies required for the precise detection of numerous diseases. Although diagnoses based on acid recognition some most efficient procedures, these tests often require expensive equipment skilled professionals. Recent advancements in diagnostic innovations, particularly those clustered regularly interspaced short palindromic repeats (CRISPR), aim to provide thorough screening at homes, clinics, field. In comparison traditional techniques like PCR, CRISPR/Cas-based detection, using single-stranded trans-cleavage abilities Cas12 or Cas13, shows significant potential as a tool. It offers benefits such attomolar-level sensitivity, single-base precision, rapid turnover rates. Both Cas enzymes demonstrate exceptional specificity holding substantial promise disease beyond. Consequently, various amplification-free methods have emerged, aiming maintain sensitivity despite absence pre-amplification. This allows non-nucleic targets facilitates integration into point-of-care settings. Review highlights current advances CRISPR/Cas systems investigates their utility Furthermore, mechanisms alternative CRISPR-based other molecules, aside from acids, diagnosis will also be briefly discussed.

Language: Английский

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Future applications of host direct therapies for infectious disease treatment

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: Oct. 1, 2024

New and emerging pathogens, such as SARS-CoV2 have highlighted the requirement for threat agnostic therapies. Some antibiotics or antivirals can demonstrate broad-spectrum activity against pathogens in same family genus but efficacy quickly reduce due to their specific mechanism of action ability disease causing agent evolve. This has led generation antimicrobial resistant strains, making infectious diseases more difficult treat. Alternative approaches therefore need be considered, which include exploring utility Host-Directed Therapies (HDTs). is a growing area with huge potential difficulties arise complexity profiles. For example, HDT given early during infection may not appropriate effective when become chronic patient intensive care. With understanding immune function, new treatment could allow targeting pathways augment diminish host response, dependent upon profile, bespoke therapeutic management plans. review highlights promising approved HDTs that manipulate system throughout spectrum disease, particular viral bacterial demonstrates how advantages will soon outweigh side effects.

Language: Английский

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Interferonopathies: From concept to clinical practice

Best Practice & Research Clinical Rheumatology, Journal Year: 2024, Volume and Issue: unknown, P. 101975 - 101975

Published: Aug. 1, 2024

The horror autoinflammaticus derived from aberrant type I interferon secretion determines a special group of autoinflammatory diseases named interferonopathies. Diverse mechanisms involved in nucleic acids sensing, metabolizing or the lack signaling retro-control are responsible for phenotypes associated to Aicardi-Goutières Syndrome (AGS), Proteasome-Associated Autoinflammatory Diseases (PRAAS), STING-Associated Vasculopathy with Infancy Onset (SAVI) and certain forms monogenic Systemic lupus erythematosus (SLE). This review approaches interferonopathies basic immunogenetic concept diagnosis treatment.

Language: Английский

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DNA sensors in metabolic and cardiovascular diseases: Molecular mechanisms and therapeutic prospects

Immunological Reviews, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 19, 2024

Summary DNA sensors generally initiate innate immune responses through the production of type I interferons. While extensively studied for host defense against invading pathogens, emerging evidence highlights involvement in metabolic and cardiovascular diseases. Elevated levels modified, damaged, or ectopically localized self‐DNA non‐self‐DNA have been observed patients animal models with obesity, diabetes, fatty liver disease, disease. The accumulation cytosolic aberrantly activates signaling pathways, driving pathological progression these disorders. This review roles specific sensors, such as cyclic AMP‐GMP synthase stimulator interferon genes (cGAS‐STING), absent melanoma 2 (AIM2), toll‐like receptor 9 (TLR9), gamma‐inducible protein 16 (IFI16), DNA‐dependent kinase (DNA‐PK), DEAD‐box helicase 41 (DDX41) various We explore how pathways both non‐immune cells contribute to development Furthermore, we discuss intricate interplay between stress responses, offering insights into potential therapeutic targets managing Understanding mechanisms sensor contexts provides a foundation developing novel interventions aimed at mitigating impact pervasive health issues.

Language: Английский

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Portable, Quantitative, Real-time Isothermal Nucleic Acid Amplification Test Using Microfluidic Device-Coupled UV-LED Photodiode Detector

Biosensors and Bioelectronics, Journal Year: 2025, Volume and Issue: unknown, P. 117194 - 117194

Published: Jan. 1, 2025

Language: Английский

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Innate Immune Sensors and Cell Death—Frontiers Coordinating Homeostasis, Immunity, and Inflammation in Skin

Viruses, Journal Year: 2025, Volume and Issue: 17(2), P. 241 - 241

Published: Feb. 10, 2025

The skin provides a life-sustaining interface between the body and external environment. A dynamic communication among immune non-immune cells in is essential to ensure homeostasis. Dysregulated cellular can lead manifestation of inflammatory conditions. In this review, we will focus on following two key frontiers skin: innate sensors cell death, as well their crosstalk context homeostasis inflammation. This review highlight recent advancements mechanisms how these pathways integrate signals orchestrate immunity, focusing diseases infections mice humans.

Language: Английский

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TMPRSS2 expression in oral mucosal cells induced by transfected double-stranded RNA and IL-1β

Journal of Oral Biosciences, Journal Year: 2025, Volume and Issue: unknown, P. 100619 - 100619

Published: Feb. 1, 2025

Language: Английский

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LPS binding caspase activation and recruitment domains (CARDs) are bipartite lipid binding modules

Science Advances, Journal Year: 2025, Volume and Issue: 11(10)

Published: March 7, 2025

Caspase-11 is an innate immune pattern recognition receptor (PRR) that detects cytosolic bacterial lipopolysaccharides (LPS) through its caspase activation and recruitment domain (CARD). also eukaryotic (i.e., self) lipids. This observation raises the question of whether common or distinct mechanisms govern interactions with self- nonself-lipids. In this study, using biochemical, computational, cell-based assays, we report caspase-11 CARD functions as a bipartite lipid-binding module. Distinct regions within bind to phosphate groups long acyl chains Self-lipid binding capability conserved across numerous homologs orthologs. The symmetry in nonself-lipid detection enabled us engineer LPS-binding de novo, ancestral CARD-like present fish Amphilophus citrinellus . These findings offer insights into molecular basis LPS by highlight fundamental likely inseparable relationship between self nonself discrimination.

Language: Английский

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