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目前正在临床试验的新型蛋白质降解治疗药物的分子设计。

Molecular Design of Novel Protein-Degrading Therapeutics Agents Currently in Clinical Trial.

作者信息

Kacin Ela, Sewduth Raj Nayan

机构信息

VIB-KU Leuven Center for Cancer Biology (VIB), 3000 Leuven, Belgium.

出版信息

Pharmaceutics. 2025 Jun 5;17(6):744. doi: 10.3390/pharmaceutics17060744.


DOI:10.3390/pharmaceutics17060744
PMID:40574056
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12196083/
Abstract

The landscape of clinical trials aimed at targeting specific proteins has experienced significant advancements, presenting promising opportunities for the development of effective therapeutics across a range of diseases. These trials focus on the investigation of modulation of protein functions, utilizing innovative technologies such as PROTACs (Proteolysis-Targeting Chimeras) and other protein degraders. These innovative approaches aim to address previously undruggable targets, enhancing the specificity and efficacy of treatments. The current landscape of clinical trials encompasses a diverse array of therapeutic areas, including oncology, autoimmune diseases, and neurological disorders. For instance, drugs like ARV-471 and ARV-110 are in advanced phases for treating metastatic breast cancer and prostate cancer, respectively, by targeting estrogen and androgen receptors. Early-phase trials explored the potential of targeting proteins like IKZF1/3 in multiple myeloma and IRAK4 in autoimmune diseases. The conducted trials not only emphasize the therapeutic potential of protein degradation but also highlight the challenges associated with bioavailability, stability, and delivery mechanisms. As these clinical trials advance, they possess the potential to transform treatment paradigms, providing renewed hope for patients facing complex and refractory conditions.

摘要

旨在靶向特定蛋白质的临床试验领域取得了重大进展,为一系列疾病开发有效疗法带来了充满希望的机遇。这些试验专注于研究蛋白质功能的调节,利用诸如PROTACs(蛋白酶靶向嵌合体)和其他蛋白质降解剂等创新技术。这些创新方法旨在攻克以前难以成药的靶点,提高治疗的特异性和疗效。目前的临床试验领域涵盖了各种各样的治疗领域,包括肿瘤学、自身免疫性疾病和神经疾病。例如,ARV - 471和ARV - 110等药物分别处于治疗转移性乳腺癌和前列腺癌的后期阶段,它们通过靶向雌激素和雄激素受体发挥作用。早期试验探索了在多发性骨髓瘤中靶向IKZF1/3以及在自身免疫性疾病中靶向IRAK4等蛋白质的潜力。所进行的试验不仅强调了蛋白质降解的治疗潜力,也突出了与生物利用度、稳定性和递送机制相关的挑战。随着这些临床试验的推进,它们有可能改变治疗模式,为面临复杂和难治病症的患者带来新的希望。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/e807fa5e35be/pharmaceutics-17-00744-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/dd756d4bc8f3/pharmaceutics-17-00744-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/b707eda94e30/pharmaceutics-17-00744-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/e807fa5e35be/pharmaceutics-17-00744-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/dd756d4bc8f3/pharmaceutics-17-00744-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/b707eda94e30/pharmaceutics-17-00744-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2973/12196083/e807fa5e35be/pharmaceutics-17-00744-g003.jpg

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Molecular Design of Novel Protein-Degrading Therapeutics Agents Currently in Clinical Trial.

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本文引用的文献

[1]
The Peptide PROTAC Modality: A New Strategy for Drug Discovery.

MedComm (2020). 2025-3-24

[2]
Conquering PROTAC molecular design and drugability.

Bioanalysis. 2025-4

[3]
An updated review on the role of small molecules in mediating protein degradation.

Eur J Med Chem. 2025-4-5

[4]
Expanding the reaction toolbox for nanoscale direct-to-biology PROTAC synthesis and biological evaluation.

RSC Med Chem. 2024-12-23

[5]
Development of PROTACs using computational approaches.

Trends Pharmacol Sci. 2024-12

[6]
Powering up targeted protein degradation through active and passive tumour-targeting strategies: Current and future scopes.

Pharmacol Ther. 2024-11

[7]
Computational methods and key considerations for in silico design of proteolysis targeting chimera (PROTACs).

Int J Biol Macromol. 2024-10

[8]
Structural and Physicochemical Features of Oral PROTACs.

J Med Chem. 2024-8-8

[9]
Discovery of KT-413, a Targeted Protein Degrader of IRAK4 and IMiD Substrates Targeting MYD88 Mutant Diffuse Large B-Cell Lymphoma.

J Med Chem. 2024-7-11

[10]
Oral Estrogen Receptor PROTAC Vepdegestrant (ARV-471) Is Highly Efficacious as Monotherapy and in Combination with CDK4/6 or PI3K/mTOR Pathway Inhibitors in Preclinical ER+ Breast Cancer Models.

Clin Cancer Res. 2024-8-15

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