Proteolysis-Targeting Chimeras (PROTACs) are heterobifunctional small-molecules that can promote the rapid and selective proteasome-mediated degradation of intracellular proteins through the recruitment of E3 ligase complexes to non-native protein substrates. The catalytic mechanism of action of PROTACs represents an exciting new modality in drug discovery that offers several potential advantages over traditional small-molecule inhibitors, including the potential to deliver pharmacodynamic (PD) efficacy which extends beyond the detectable pharmacokinetic (PK) presence of the PROTAC, driven by the synthesis rate of the protein. Herein we report the identification and development of PROTACs that selectively degrade Receptor-Interacting Serine/Threonine Protein Kinase 2 (RIPK2) and demonstrate in vivo degradation of endogenous RIPK2 in rats at low doses and extended PD that persists in the absence of detectable compound. This disconnect between PK and PD, when coupled with low nanomolar potency, offers the potential for low human doses and infrequent dosing regimens with PROTAC medicines.

靶向蛋白水解嵌合体（PROTAC）是异双功能小分子，可以通过将E3连接酶复合物募集到非天然蛋白底物上来促进蛋白酶体介导的胞内蛋白的快速和选择性降解。PROTAC的催化作用机制代表了一种令人兴奋的药物发现新形式，与传统的小分子抑制剂相比，具有多种潜在的优势，包括传递药效（PD）功效的潜力超出了PROTAC的可检测药代动力学（PK）范围，由蛋白质的合成速率驱动。在本文中，我们报告了P​​ROTAC的鉴定和开发，该PROTAC可选择性降解受体相互作用的丝氨酸/苏氨酸蛋白激酶2（RIPK2），并证明了低剂量大鼠内源性RIPK2的体内降解以及在没有可检测化合物的情况下持续存在的PD延长。PK和PD之间的这种脱钩，再加上低纳摩尔效价，为使用PROTAC药物的低人剂量和不频繁给药方案提供了潜力。