Our collaborative work with Scott Lokey's Lab at UCSC on PROTAC structure-permeability relationships is now published in ACS Med Chem Lett

  • ToC graphics
  • Figure 1. Physicochemical properties of protein-targeting small molecules and model compounds.
  • Figure 2. Physicochemical properties of “AT” and “MZ” PROTACs.
  • Figure 3. MZ1 ternary complex with VHL and Brd4 (PDB:5T35).
  • Figure 4. Fluorescence polarization (FP)-derived Kd of amide to ester substitution in SLX compounds
  • Figure 5. Physicochemical properties of “MZP” and “CM/CMP” PROTACs
  • Figure 6. PROTAC permeability and LPE

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

Authors: Victoria G. Klein, Chad E. Townsend, Andrea Testa, Michael Zengerle, Chiara Maniaci, Scott J. Hughes, Kwok-Ho Chan, Alessio Ciulli, and R. Scott Lokey


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.


Congrats to Tori Klein in Scott Lokey's lab for her work on our PROTAC molecules!