Hendrick Charles E, Jorgensen Jeff R, Chaudhry Charu, Strambeanu Iulia I, Brazeau Jean-Francois, Schiffer Jamie, Shi Zhicai, Venable Jennifer D, Wolkenberg Scott E
Discovery Chemistry, Therapeutics Discovery, Janssen Research & Development, LLC,Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
Discovery Technology and Molecular Pharmacology, Therapeutics Discovery, Janssen Research & Development, LLC, Welsh & McKean Roads, Spring House, Pennsylvania 19477, United States.
ACS Med Chem Lett. 2022 Jun 20;13(7):1182-1190. doi: 10.1021/acsmedchemlett.2c00124. eCollection 2022 Jul 14.
A platform to accelerate optimization of proteolysis targeting chimeras (PROTACs) has been developed using a direct-to-biology (D2B) approach with a focus on linker effects. A large number of linker analogs-with varying length, polarity, and rigidity-were rapidly prepared and characterized in four cell-based assays by streamlining time-consuming steps in synthesis and purification. The expansive dataset informs on linker structure-activity relationships (SAR) for in-cell E3 ligase target engagement, degradation, permeability, and cell toxicity. Unexpected aspects of linker SAR was discovered, consistent with literature reports on "linkerology", and the method dramatically speeds up empirical optimization. Physicochemical property trends emerged, and the platform has the potential to rapidly expand training sets for more complex prediction models. In-depth validation studies were carried out and confirm the D2B platform is a valuable tool to accelerate PROTAC design-make-test cycles.
利用直接生物学（D2B）方法，开发了一个加速蛋白酶靶向嵌合体（PROTAC）优化的平台，重点关注连接子效应。通过简化合成和纯化中耗时的步骤，快速制备了大量具有不同长度、极性和刚性的连接子类似物，并在四种基于细胞的测定中进行了表征。这个庞大的数据集为细胞内E3连接酶靶点结合、降解、通透性和细胞毒性的连接子构效关系（SAR）提供了信息。发现了连接子SAR的意外方面，这与关于“连接子学”的文献报道一致，并且该方法极大地加速了经验优化。出现了物理化学性质趋势，该平台有潜力迅速扩展更复杂预测模型的训练集。进行了深入的验证研究，证实D2B平台是加速PROTAC设计-制造-测试循环的有价值工具。
