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ID: ALA4725409

Journal: ACS Med Chem Lett

Title: Understanding and Improving the Membrane Permeability of VH032-Based PROTACs.

Authors: Klein VG,Townsend CE,Testa A,Zengerle M,Maniaci C,Hughes SJ,Chan KH,Ciulli A,Lokey RS

Abstract: Proteolysis targeting chimeras (PROTACs) are catalytic heterobifunctional molecules that can selectively degrade a protein of interest by recruiting a ubiquitin E3 ligase to the target, leading to its ubiquitylation and degradation by the proteasome. Most degraders lie outside the chemical space associated with most membrane-permeable drugs. Although many PROTACs have been described with potent activity in cells, our understanding of the relationship between structure and permeability in these compounds remains limited. Here, we describe a label-free method for assessing the permeability of several VH032-based PROTACs and their components by combining a parallel artificial membrane permeability assay (PAMPA) and a lipophilic permeability efficiency (LPE) metric. Our results show that the combination of these two cell-free membrane permeability assays provides new insight into PROTAC structure-permeability relationships and offers a conceptual framework for predicting the physicochemical properties of PROTACs in order to better inform the design of more permeable and more effective degraders.

CiteXplore: 32939229

DOI: 10.1021/acsmedchemlett.0c00265