Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation,Chemical Society Reviews

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Proteolysis-targeting chimera (PROTAC) delivery system: advancing protein degraders towards clinical translation
Chemical Society Reviews ( IF 40.4 ) Pub Date : 2022-06-17 , DOI: 10.1039/d1cs00762a
Yu Chen _{1,

2,

3} , Ira Tandon ₁ , William Heelan ₁ , Yixin Wang _{1,

2,

3} , Weiping Tang ₁ , Quanyin Hu _{1,

2,

3}

Affiliation

Proteolysis Targeting Chimeras (PROTACs), an emerging therapeutic entity designed to degrade target proteins by hijacking the ubiquitin–proteasome system, have the potential to revolutionize the healthcare industry. The broad applicability of this protein degradation strategy has been verified with a few E3 ligases and a variety of distinct targets through the construction of modular chimeric structures. Despite recent efforts to promote the use of PROTACs for clinical applications, most PROTACs do not make it beyond the preclinical stage of drug development. There are several reasons that prevent PROTACs from reaching the market, and the inadequate delivery to the target site is one of the most challenging hurdles. With the increasing need for accelerating the translational process, combining the concepts of PROTACs and delivery systems has been explored to enhance the in vivo performance of PROTACs. These improved delivery strategies can eliminate unfavorable physicochemical properties of PROTACs, improve their targetability, and decrease their off-target side effects. The integration of powerful PROTACs and versatile delivery systems will inaugurate a burgeoning orientation for the field of targeted protein degradation. In this review, we will survey the latest progress in improving the in vivo degradation efficacy of PROTACs through delivery strategies, outline design principles for PROTAC-based delivery systems, discuss the current challenges with PROTACs, and outlook future opportunities in this field.

中文翻译：

蛋白水解靶向嵌合体 (PROTAC) 递送系统：推动蛋白质降解剂走向临床转化

蛋白水解靶向嵌合体 (PROTAC) 是一种新兴的治疗实体，旨在通过劫持泛素-蛋白酶体系统来降解靶蛋白，有可能彻底改变医疗保健行业。通过构建模块化嵌合结构，这种蛋白质降解策略的广泛适用性已通过一些 E3 连接酶和各种不同的靶标得到了验证。尽管最近努力促进 PROTAC 在临床应用中的使用，但大多数 PROTAC 并未超越药物开发的临床前阶段。阻碍 PROTAC 进入市场的原因有多种，而目标地点的交付不足是最具挑战性的障碍之一。随着对加速转化过程的需求不断增加，人们探索将 PROTAC 和递送系统的概念相结合以增强PROTAC 的体内性能。这些改进的递送策略可以消除 PROTAC 不利的理化特性，提高其靶向性，并减少其脱靶副作用。强大的 PROTAC 和多功能递送系统的集成将为靶向蛋白质降解领域开辟一个新兴方向。在这篇综述中，我们将调查通过递送策略提高PROTAC 体内降解功效的最新进展，概述基于 PROTAC 的递送系统的设计原则，讨论 PROTAC 当前的挑战，并展望该领域的未来机遇。

更新日期：2022-06-17

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