Targeted protein degradation (TPD) strategies have revolutionized how scientists tackle challenging protein targets deemed undruggable with traditional small molecule inhibitors. Many promising campaigns to inhibit proteins have failed due to factors surrounding inhibition selectivity and targeting of compounds to specific tissues and cell types. One of the major improvements that PROTAC (proteolysis targeting chimera) and molecular glue technology can exert is highly selective control of target inhibition. Multiple studies have shown that PROTACs can gain selectivity for their protein targets beyond that of their parent ligands via optimization of linker length and stabilization of ternary complexes. Due to the bifunctional nature of PROTACs, the tissue selective nature of E3 ligases can be exploited to uncover novel targeting mechanisms. In this review, we provide critical analysis of the recent progress towards making selective PROTAC molecules and new PROTAC technologies that will continue to push the boundaries of achieving selectivity. These efforts have wide implications in the future of treating disease as they will broaden the possible targets that can be addressed by small molecules, like undruggable proteins or broadly active targets that would benefit from degradation in specific tissue types.

中文翻译：

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PROTAC 降解剂的靶标和组织选择性

靶向蛋白质降解 (TPD) 策略彻底改变了科学家处理被认为无法用传统小分子抑制剂治疗的具有挑战性的蛋白质靶点的方式。由于围绕抑制选择性和化合物靶向特定组织和细胞类型的因素，许多有前途的蛋白质抑制运动都失败了。PROTAC（靶向嵌合体的蛋白水解）和分子胶技术可以发挥的主要改进之一是对目标抑制的高度选择性控制。多项研究表明，PROTAC 可以通过连接长度的优化和三元复合物的稳定性。由于 PROTAC 的双功能特性，E3 连接酶的组织选择性可用于发现新的靶向机制。在这篇综述中，我们对最近在制造选择性 PROTAC 分子和新的 PROTAC 技术方面取得的进展进行了批判性分析，这些技术将继续突破实现选择性的界限。这些努力对未来的疾病治疗具有广泛的意义，因为它们将拓宽小分子可以解决的可能目标，例如不可药物化的蛋白质或将受益于特定组织类型降解的广泛活性目标。