Induced Proximity Platform, Amgen, Thousand Oaks, CA 91320, USA.
Genome Analysis Unit, Amgen, Thousand Oaks, CA 91320, USA.
Chem Soc Rev. 2022 Jul 18;51(14):5740-5756. doi: 10.1039/d2cs00200k.
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 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.
靶向蛋白降解（TPD）策略彻底改变了科学家们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标的方式。由于抑制选择性以及化合物靶向特定组织和细胞类型的因素，许多有前途的抑制蛋白质的研究都失败了。PROTAC（蛋白水解靶向嵌合体）和分子胶技术可以带来的主要改进之一是对靶标抑制的高度选择性控制。多项研究表明，PROTAC 可以获得比其母体配体更高的蛋白质靶标选择性，优化接头长度和三元复合物的稳定性。由于 PROTAC 的双功能性质，可以利用 E3 连接酶的组织选择性来揭示新的靶向机制。在这篇综述中，我们对实现选择性 PROTAC 分子的最新进展以及将继续推动实现选择性的新 PROTAC 技术进行了批判性分析。这些努力在治疗疾病的未来具有广泛的意义，因为它们将扩大可以通过小分子治疗的可能靶标，例如不可成药的蛋白质或广泛活跃的靶标，这些靶标在特定组织类型中降解将受益。
