Department of Chemistry, New York University, New York, NY 10003, USA.
Department of Chemistry, Ludwig Maximilians University of Munich, 81377 Munich, Germany.
Sci Adv. 2020 Feb 21;6(8):eaay5064. doi: 10.1126/sciadv.aay5064. eCollection 2020 Feb.
PROTACs (PROteolysis TArgeting Chimeras) are bifunctional molecules that target proteins for ubiquitylation by an E3 ligase complex and subsequent degradation by the proteasome. They have emerged as powerful tools to control the levels of specific cellular proteins. We now introduce photoswitchable PROTACs that can be activated with the spatiotemporal precision that light provides. These trifunctional molecules, which we named PHOTACs (PHOtochemically TArgeting Chimeras), consist of a ligand for an E3 ligase, a photoswitch, and a ligand for a protein of interest. We demonstrate this concept by using PHOTACs that target either BET family proteins (BRD2,3,4) or FKBP12. Our lead compounds display little or no activity in the dark but can be reversibly activated with different wavelengths of light. Our modular approach provides a method for the optical control of protein levels with photopharmacology and could lead to new types of precision therapeutics that avoid undesired systemic toxicity.
PROTACs（蛋白水解靶向嵌合体）是一种双功能分子，可通过 E3 连接酶复合物靶向蛋白质进行泛素化，随后被蛋白酶体降解。它们已成为控制特定细胞蛋白水平的有力工具。我们现在引入光可激活的 PROTACs，它们可以提供光的时空精度来进行激活。这些三功能分子，我们称之为 PHOTACs（光化学靶向嵌合体），由 E3 连接酶的配体、光开关和感兴趣的蛋白质的配体组成。我们通过使用靶向 BET 家族蛋白（BRD2、3、4）或 FKBP12 的 PHOTACs 来证明这一概念。我们的先导化合物在黑暗中几乎没有或没有活性，但可以用不同波长的光可逆激活。我们的模块化方法为光药理学的蛋白质水平的光学控制提供了一种方法，并可能导致避免不必要的全身毒性的新型精准治疗药物。
