A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment DOI Creative Commons
Lei Wang,

Yong Ke,

Qunye He

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 15(4), P. 1238 - 1254

Published: Dec. 31, 2024

Rationale: Proteolysis Targeting Chimeras (PROTACs) are bifunctional compounds that have been extensively studied for their role in targeted protein degradation (TPD).The capacity to degrade validated or undruggable targets provides PROTACs with significant potency cancer therapy.However, the clinical application of is limited by poor vivo and unfavorable pharmacokinetic properties.Methods: In this study, a novel degrader-antibody conjugate (DAC) was developed conjugating BRD4-degrading PROTAC ROR1 (receptor tyrosine kinase-like orphan receptor 1) antibody.The vitro affinity, internalization efficacy, degradation, cytotoxic activity DAC were assessed.The pharmacokinetics, antitumor activity, acute toxicity evaluated mouse models.RNA sequencing (RNA-seq) immunohistochemistry performed analyze therapeutic efficacy mediated combination anti-mouse programmed cell death 1 (αmPD1) mAb. Results:The exhibited strong cytotoxicity following antigen binding internalization.Compared unconjugated PROTAC, demonstrated improved pharmacokinetics potent PC3 MDA-MB-231 xenograft models.Furthermore, enhanced immune infiltration within solid tumors observed when combined αmPD-1 mAb C57BL/6J mice.RNA revealed response associated treatment related tumor microenvironment modulation, including upregulation Th1-biased cytokines.Moreover, favorable safety profile an study.Conclusions: These results indicate promising candidate tumor-specific effective therapy.

Language: Английский

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives DOI Open Access
Jiahao Li, Gong Chen, Haiting Zhou

et al.

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

Citations

20
Discovery of High-Affinity SMARCA2/4 Bromodomain Ligands and Development of Potent and Exceptionally Selective SMARCA2 PROTAC Degraders DOI

Lingying Leng,

Wenbin Tu,

Lin Yang

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 2, 2025

In the SWI/SNF chromatin-remodeling complex, mutually exclusive catalytic ATPase subunits SMARCA2 and SMARCA4 proteins have a synthetic-lethal relationship. Selectively targeting for degradation is promising new therapeutic strategy human cancers harboring inactivated mutated SMARCA4. this study, we report design, synthesis, biological evaluation of novel SMARCA2/4 ligands our subsequent design PROTAC degraders using high-affinity SMARCA VHL-1 ligands. Our efforts led to discovery bromodomain development potent selective degrader highly PBRM1 degrader.

Language: Английский

Citations

1
Prodrug Approach as a Strategy to Enhance Drug Permeability DOI Creative Commons
Mariana Moraes Dionysio de Souza, Ana Luísa Rodriguez Gini,

Jhonnathan Alves Moura

et al.

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

Citations

0
Application of Artificial Intelligence and Computational Biology in Protein Drug Development DOI Creative Commons
Jiacheng Jiang, Wen Li, Weiran Huang

et al.

Pharmaceutical Fronts, Journal Year: 2025, Volume and Issue: unknown

Published: March 6, 2025

Abstract Protein drugs have evolved into a primary category of biological drugs. Despite the impressive achievements, protein therapeutics still face several challenges, including potential immunogenicity, druggability, and high costs. In recent years, artificial intelligence (AI) computational biology emerged as powerful tools to overcome these challenges reshape drug development pipeline. This review underscores pivotal role AI in advancing development, analysis phage libraries, application computer-aided techniques for new display systems, optimization design novel antibody–drug conjugates, nanobodies, cytokines. The delves use predicting pharmacological properties therapeutics, providing comprehensive overview transformative impact approaches areas.

Language: Английский

Citations

0
Integrating Proteolysis‐Targeting Chimeras (PROTACs) with Delivery Systems for More Efficient and Precise Targeted Protein Degradation DOI

Jiachan Lin,

Zirui Chen, Dan Zhang

et al.

Macromolecular Rapid Communications, Journal Year: 2025, Volume and Issue: unknown

Published: April 4, 2025

Targeted protein degradation (TPD) using the proteolysis-targeting chimeras (PROTACs) is emerging as a revolutionary technology, offering potential strategy for cancer treatment by inducing of overexpressed oncogenic proteins in tumors. PROTACs function recruiting E3 ligases and utilizing ubiquitin-proteasome pathway (UPS) to catalyze target proteins. Compared traditional small molecules inhibitors, exhibit enhanced selectivity, ability overcome drug resistance, traditionally deemed "undruggable". However, poor water solubility low cellular permeability significantly limit their pharmacokinetic properties, while systemic toxicity may hinder clinical application. To address these limitations, strategies that integrate with delivery systems are gaining attention. This review summarizes latest advancements various enhance vivo efficacy reduce off-target effects PROTACs, including prototype nanoparticles, covalent modification-based prodrug strategies, innovative multi-headed designs, microneedle systems, discussing design principles associated challenges. The combination potent multifunctional holds promise accelerating translation improving therapeutic treatment.

Language: Английский

Citations

0
Comprehensive approaches to preclinical evaluation of monoclonal antibodies and their next-generation derivatives DOI

Santanu Singh,

Kajal Kachhawaha,

Sumit K. Singh

et al.

Biochemical Pharmacology, Journal Year: 2024, Volume and Issue: 225, P. 116303 - 116303

Published: May 24, 2024

Language: Английский

Citations

1
Precision-engineered PROTACs minimize off-tissue effects in cancer therapy DOI Creative Commons

Jianghua Shi,

Luo Wang,

Xuanwei Zeng

et al.

Frontiers in Molecular Biosciences, Journal Year: 2024, Volume and Issue: 11

Published: Nov. 22, 2024

Proteolysis-targeting chimeras (PROTACs) offer a groundbreaking approach to selectively degrade disease-related proteins by utilizing the ubiquitin-proteasome system. While this strategy shows great potential in preclinical and clinical settings, off-tissue effects remain major challenge, leading toxicity healthy tissues. This review explores recent advancements aimed at improving PROTAC specificity, including tumor-specific ligand-directed PROTACs, pro-PROTACs activated tumor environments, E3 ligase overexpression strategies. Innovations such as PEGylation nanotechnology also play role optimizing efficacy. These developments hold promise for safer, more effective cancer therapies, though challenges translation.

Language: Английский

Citations

0
A novel ROR1-targeting antibody-PROTAC conjugate promotes BRD4 degradation for solid tumor treatment DOI Creative Commons
Lei Wang,

Yong Ke,

Qunye He

et al.

Theranostics, Journal Year: 2024, Volume and Issue: 15(4), P. 1238 - 1254

Published: Dec. 31, 2024

Rationale: Proteolysis Targeting Chimeras (PROTACs) are bifunctional compounds that have been extensively studied for their role in targeted protein degradation (TPD).The capacity to degrade validated or undruggable targets provides PROTACs with significant potency cancer therapy.However, the clinical application of is limited by poor vivo and unfavorable pharmacokinetic properties.Methods: In this study, a novel degrader-antibody conjugate (DAC) was developed conjugating BRD4-degrading PROTAC ROR1 (receptor tyrosine kinase-like orphan receptor 1) antibody.The vitro affinity, internalization efficacy, degradation, cytotoxic activity DAC were assessed.The pharmacokinetics, antitumor activity, acute toxicity evaluated mouse models.RNA sequencing (RNA-seq) immunohistochemistry performed analyze therapeutic efficacy mediated combination anti-mouse programmed cell death 1 (αmPD1) mAb. Results:The exhibited strong cytotoxicity following antigen binding internalization.Compared unconjugated PROTAC, demonstrated improved pharmacokinetics potent PC3 MDA-MB-231 xenograft models.Furthermore, enhanced immune infiltration within solid tumors observed when combined αmPD-1 mAb C57BL/6J mice.RNA revealed response associated treatment related tumor microenvironment modulation, including upregulation Th1-biased cytokines.Moreover, favorable safety profile an study.Conclusions: These results indicate promising candidate tumor-specific effective therapy.

Language: Английский

Citations

0