CRBN‐PROTACs in Cancer Therapy: From Mechanistic Insights to Clinical Applications

Chemical Biology & Drug Design, Journal Year: 2024, Volume and Issue: 104(5)

Published: Nov. 1, 2024

Cereblon (CRBN), a member of the E3 ubiquitin ligase complex, has gained significant attention as therapeutic target in cancer. CRBN regulates degradation various proteins cancer progression, including transcription factors and signaling molecules. PROTACs (proteolysis-targeting chimeras) are novel approach that uses cell's system to remove disease-causing selectively. CRBN-dependent work by tagging harmful for destruction through ubiquitin-proteasome system. This strategy offers several advantages over traditional protein inhibition methods, potential overcome drug resistance. Recent progress developing CRBN-based shown promising preclinical results both hematologic malignancies solid tumors. Additionally, have enhanced our understanding CRBN's role cancer, potentially serving biomarkers patient stratification predicting responses. In this review, we delineate mechanisms action (CRBN-PROTACs), summarize recent advances clinical applications, provide perspective on future development.

Language: Английский

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Cynthichlorine Extracted from Ascidian Cynthia savignyi from Djibouti: Optimization of Extraction, In Vitro Anticancer Profiling, and In Silico Approach

Marine Drugs, Journal Year: 2025, Volume and Issue: 23(4), P. 172 - 172

Published: April 16, 2025

This work focuses on the extraction of cynthichlorine from ascidian Cynthia savignyi, a molecule that has potential promise as an anticancer agent. The main objective was to optimize conditions and evaluate cytotoxic activity in tumor cell lines. Two methods, maceration Soxhlet extraction, were compared, with showing significantly higher yield (2.2 ± 0.2%) compared (1.0 0.2%). An optimization factors influencing performed using Box–Behnken method, temperature time have negative impact yield, optimal being below 25 °C those 12 h. Cytotoxic assessment revealed marked inhibition growth all tested lines (U87-MG, U2OS, NCI-N87, HCT116, A2780), IC50 values ranging 0.162 µg/mL U87-MG 0.576 NCI-N87. Finally, computational analysis showed exhibits high electronic stability notable affinity for some biological targets, including NM23-H2, suggesting its targeted therapy cancer treatment. These results pave way future studies therapeutic use cynthichlorine.

Language: Английский

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Current perspectives in drug targeting intrinsically disordered proteins and biomolecular condensates

BMC Biology, Journal Year: 2025, Volume and Issue: 23(1)

Published: May 5, 2025

Intrinsically disordered proteins (IDPs) and biomolecular condensates are critical for cellular processes physiological functions. Abnormal can cause diseases such as cancer neurodegenerative disorders. IDPs, including intrinsically regions (IDRs), were previously considered undruggable due to their lack of stable binding pockets. However, recent evidence indicates that targeting them influence processes. This review explores current strategies target IDPs condensates, potential improvements, the challenges opportunities in this evolving field.

Language: Английский

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Proteolysis targeting chimeras (PROTACs) in oncology: a review of patents and regulatory considerations

Pharmaceutical Patent Analyst, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 13

Published: May 15, 2025

Proteolysis Targeting Chimeras (PROTACs) represents a groundbreaking advancement in drug discovery and targeted protein degradation. Unlike traditional small-molecule inhibitors, PROTACs leverage the cell's natural degradation machinery to selectively degrade pathogenic proteins, offering significant therapeutic potential for previously undruggable targets complex diseases such as cancer neurodegenerative disorders. Understanding regulatory landscape governing their approval is crucial development accelerates. This review provides an overview of recent patents, considerations, emerging concerns, future perspectives management. From perspective, present unique challenges opportunities. Their dual-functional nature requires nuanced approach classification approval, blending biologic frameworks. Specific guidelines addressing pharmacokinetic pharmacodynamic profiles are needed. Comprehensive preclinical evaluation robust clinical trial designs essential manage off-target effects immunogenic responses. The collaboration between bodies, academia, industry establishing clear pathway PROTAC approval. Future considerations must account advancements technology ensure safe effective therapies reach patients. While hold immense promise, journey tailored rigorous realize full potential.

Language: Английский

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Computational strategies for the design of proteolysis targeting chimera degraders: Artificial intelligence enabled PROTAC design

Annual reports in medicinal chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 1, 2024

Language: Английский

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Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions

Drug Delivery and Translational Research, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 29, 2024

Language: Английский

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