Direct-to-Biology Accelerates PROTAC Synthesis and the Evaluation of Linker Effects on Permeability and Degradation.

ABSTRACT: 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 rapidl

SUBMITTER: Hendrick CE 

PROVIDER: S-EPMC9290060 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature