New-generation advanced PROTACs as potential therapeutic agents in cancer therapy

Molecular Cancer, Journal Year: 2024, Volume and Issue: 23(1)

Published: May 21, 2024

Abstract Proteolysis-targeting chimeras (PROTACs) technology has garnered significant attention over the last 10 years, representing a burgeoning therapeutic approach with potential to address pathogenic proteins that have historically posed challenges for traditional small-molecule inhibitors. PROTACs exploit endogenous E3 ubiquitin ligases facilitate degradation of interest (POIs) through ubiquitin–proteasome system (UPS) in cyclic catalytic manner. Despite recent endeavors advance utilization clinical settings, majority fail progress beyond preclinical phase drug development. There are multiple factors impeding market entry PROTACs, insufficiently precise favorable POIs standing out as one most formidable obstacles. Recently, there been exploration new-generation advanced including PROTAC prodrugs, biomacromolecule-PROTAC conjugates, and nano-PROTACs, improve vivo efficacy PROTACs. These improved possess capability mitigate undesirable physicochemical characteristics inherent thereby enhancing their targetability reducing off-target side effects. The will mark pivotal turning point realm targeted protein degradation. In this comprehensive review, we meticulously summarized state-of-the-art advancements achieved by these cutting-edge elucidated underlying design principles, deliberated upon prevailing encountered, provided an insightful outlook on future prospects within field.

Language: Английский

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Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5489 - 5489

Published: May 17, 2024

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies peptides, along innovative approaches use of degraders protein interaction inhibitors, which recently demonstrated clinical progress potential in overcoming resistance. Nevertheless, kinase-targeted encounter significant hurdles, including drug resistance, greatly impacts benefits patients, well concerning toxicity when combined immunotherapy, restricts full utilization current treatment modalities. Despite these challenges, development remains highly promising. The extensively studied tyrosine family has 70% its stages development, while 30% inadequately explored. Computational technologies play a vital role accelerating novel repurposing existing drugs. Recent FDA-approved SMKIs underscore importance blood-brain barrier permeability long-term patient benefits. This review provides comprehensive summary recent based mechanisms action targets. We summarize latest developments new explore emerging inhibition from perspective. Lastly, we outline obstacles future prospects inhibition.

Language: Английский

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Potential of CDC25 phosphatases in cancer research and treatment: key to precision medicine

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

Published: Jan. 19, 2024

The global burden of cancer continues to rise, underscoring the urgency developing more effective and precisely targeted therapies. This comprehensive review explores confluence precision medicine CDC25 phosphatases in context research. Precision medicine, alternatively referred as customized aims customize medical interventions by taking into account genetic, genomic, epigenetic characteristics individual patients. identification particular genetic molecular drivers driving helps both diagnostic accuracy treatment selection. utilizes sophisticated technology such genome sequencing bioinformatics elucidate differences that underlie proliferation cells, hence facilitating development therapeutic interventions. phosphatases, which play a crucial role governing progression cell cycle, have garnered significant attention potential targets for treatment. dysregulation is characteristic feature observed various types malignancies, classifying them proto-oncogenes. proteins question, operate activation Cyclin-dependent kinases (CDKs), so promoting advancement cycle. inhibitors demonstrate drugs specifically blocking activity CDKs modulating cycle malignant cells. In brief, presents potentially fruitful option augmenting research, diagnosis, treatment, with an emphasis on individualized care predicated upon patients’ profiles. highlights significance identifies promising candidates intervention. statement underscores doing thorough profiling order uncover complex

Language: Английский

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PROTAC-biomacromolecule conjugates for precise protein degradation in cancer therapy: A review

International Journal of Biological Macromolecules, Journal Year: 2024, Volume and Issue: 261, P. 129864 - 129864

Published: Jan. 30, 2024

Language: Английский

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Emerging paradigms and recent progress in targeting ErbB in cancers

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(6), P. 552 - 576

Published: May 25, 2024

The epidermal growth factor receptor (EGFR) family is a class of transmembrane proteins, highly regarded as anticancer targets due to their pivotal role in various malignancies. Standard cancer treatments targeting the ErbB receptors include tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs). Despite substantial survival benefits, achievement curative outcomes hindered by acquired resistance. Recent advancements anti-ErbB approaches, such inhibitory peptides, nanobodies, targeted-protein degradation strategies, bispecific (BsAbs), aim overcome More recently, emerging insights into cell surface interactome open new avenues for modulating signaling specific domains partners. Here, we review recent progress elucidate paradigms that underscore significance EGF domain-containing proteins (EDCPs) ErbB-targeting pathways.

Language: Английский

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Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators

Cancers, Journal Year: 2023, Volume and Issue: 15(20), P. 5009 - 5009

Published: Oct. 16, 2023

Epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitors (TKIs) have changed the landscape of lung cancer therapy. For patients who are treated with new TKIs, current median survival exceeds 3 years, substantially better than average 20 month rate only a decade ago. Unfortunately, despite initial efficacy, nearly all evolve drug resistance due to emergence either mutations or rewired signaling pathways that engage other kinases (RTKs), such as MET, HER3 and AXL. Apparently, is preceded by phase epigenetic alterations finely regulate cell cycle, bias mesenchymal phenotype activate antioxidants. Concomitantly, cells evade TKI-induced apoptosis (i.e., drug-tolerant persister cells) an intrinsic mutagenic program reminiscent SOS system deployed when bacteria exposed antibiotics. This mammalian imbalances purine-to-pyrimidine ratio, inhibits DNA repair boosts expression mutation-prone polymerases. Thus, net outcome response greater probability mutations. Deeper understanding persister-to-resister transformation, along development next-generation EGFR-specific proteolysis targeting chimeras (PROTACs), well bispecific antibodies, will permit delaying onset relapses prolonging EGFR+ cancer.

Language: Английский

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Prodrug Approach as a Strategy to Enhance Drug Permeability

Pharmaceuticals, Journal Year: 2025, Volume and Issue: 18(3), P. 297 - 297

Published: Feb. 21, 2025

Absorption and permeability are critical physicochemical parameters that must be balanced to achieve optimal drug uptake. These key factors closely linked the maximum absorbable dose required provide appropriate plasma levels of drugs. Among various strategies employed enhance solubility permeability, prodrug design stands out as a highly effective versatile approach for improving properties enabling optimization biopharmaceutical pharmacokinetic while mitigating adverse effects. Prodrugs compounds with reduced or no activity that, through bio-reversible chemical enzymatic processes, release an active parental drug. The application this technology has led significant advancements in during phase, it offers broad potential further development. Notably, approximately 13% drugs approved by U.S. Food Drug Administration (FDA) between 2012 2022 were prodrugs. In review article, we will explore describing examples market We also describe use optimize PROteolysis TArgeting Chimeras (PROTACs) using conjugation technologies. highlight some new technologies prodrugs enrich properties, contributing developing safe

Language: Английский

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Strategies to Overcome Resistance to Osimertinib in EGFR-Mutated Lung Cancer

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 2957 - 2957

Published: March 25, 2025

Non-small-cell lung cancer (NSCLC) represents the most common type of cancer. The majority patients with characterized by activating mutations in epidermal growth factor receptor (EGFR), benefit from therapies entailing tyrosine kinase inhibitors (TKIs). In this regard, osimertinib, a third-generation EGFR TKI, has greatly improved outcome for EGFR-mutated AURA and FLAURA trials displayed superiority TKI both first- second-line settings, making it drug choice treating Unfortunately, onset resistance is almost inevitable. On-target mechanisms include new (e.g., C797S) domain EGFR, while among off-target mechanisms, amplification MET or HER2, downstream signaling molecules, oncogenic fusions, phenotypic changes EMT) have been described. This review focuses on strategies that are currently being investigated, preclinical clinical to overcome including use fourth-generation TKIs, PROTACs, bispecific antibodies, ADCs, as monotherapy part combination therapies.

Language: Английский

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Protein lipidation in the tumor microenvironment: enzymology, signaling pathways, and therapeutics

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: May 7, 2025

Abstract Protein lipidation is a pivotal post-translational modification that increases protein hydrophobicity and influences their function, localization, interaction network. Emerging evidence has shown significant roles of in the tumor microenvironment (TME). However, comprehensive review this topic lacking. In review, we present an integrated in-depth literature context TME. Specifically, focus on three major modifications: S- prenylation, palmitoylation, N- myristoylation. We emphasize how these modifications affect oncogenic signaling pathways complex interplay between cells surrounding stromal immune cells. Furthermore, explore therapeutic potential targeting mechanisms cancer treatment discuss prospects for developing novel anticancer strategies disrupt lipidation-dependent pathways. By bridging with dynamics TME, our provides insights into relationship them drives initiation progression.

Language: Английский

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Targeted nanoliposomes of oncogenic protein degraders: Significant inhibition of tumor in lung-cancer bearing mice

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 376, P. 502 - 517

Published: Oct. 23, 2024

Language: Английский

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