Solution Conformations Shed Light on PROTAC Cell Permeability.
Basic Information
ID: ALA4715905
Journal: ACS Med Chem Lett
Title: Solution Conformations Shed Light on PROTAC Cell Permeability.
Authors: Atilaw Y,Poongavanam V,Svensson Nilsson C,Nguyen D,Giese A,Meibom D,Erdelyi M,Kihlberg J
Abstract: Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π-π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.
CiteXplore: 33488971
DOI: 10.1021/acsmedchemlett.0c00556
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