Kuchta Robert, Heim Christopher, Herrmann Alexander, Maiwald Samuel, Ng Yuen Lam Dora, Sosič Izidor, Keuler Tim, Krönke Jan, Gütschow Michael, Hartmann Marcus D, Steinebach Christian
Pharmaceutical Institute, Pharmaceutical & Medicinal Chemistry, University of Bonn An der Immenburg 4 Bonn D-53121 Germany
Max Planck Institute for Biology Tübingen Tübingen D-72076 Germany
RSC Chem Biol. 2023 Jan 3;4(3):229-234. doi: 10.1039/d2cb00223j. eCollection 2023 Mar 8.
The Petasis borono-Mannich reaction was employed for an alternative entry towards three-branched cereblon ligands. Such compounds are capabable of making multiple interactions with the protein surface and possess a suitable linker exit vector. The high-affinity ligands were used to assemble prototypic new molecular glues and proteolysis targeting chimeras (PROTACs) targeting BRD4 for degradation. Our results highlight the importance of multicomponent reactions (MCRs) in drug discovery and add new insights into the rapidly growing field of protein degraders.
采用Petasis硼-曼尼希反应作为合成三分支脑靶配体的另一种方法。这类化合物能够与蛋白质表面进行多重相互作用，并具有合适的连接子出口向量。高亲和力配体被用于组装针对BRD4进行降解的原型新型分子胶和蛋白酶靶向嵌合体（PROTAC）。我们的结果突出了多组分反应（MCR）在药物发现中的重要性，并为快速发展的蛋白质降解剂领域增添了新的见解。
