Amide-to-Ester Substitution as a Strategy for Optimizing PROTAC Permeability and Cellular Activity

Criteria for predicting
the druglike properties of “beyond
Rule of 5” Proteolysis Targeting Chimeras (PROTAC) degraders
are underdeveloped. PROTAC components are often combined via amide
couplings due to their reliability. Amides, however, can give rise
to poor absorption, distribution, metabolism, and excretion (ADME)
properties. We hypothesized that a bioisosteric amide-to-ester substitution
could lead to improvements in both physicochemical properties and
bioactivity. Using model compounds, bearing either amides or esters,
we identify parameters for optimal lipophilicity and permeability.
We applied these learnings to design a set of novel amide-to-ester-substituted,
VHL-based BET degraders with the goal to increase permeability. Our
ester PROTACs retained intracellular stability, were overall more
potent degraders than their amide counterparts, and showed an earlier
onset of the hook effect. These enhancements were driven by greater
cell permeability rather than improvements in ternary complex formation.
This largely unexplored amide-to-ester substitution provides a simple
strategy to enhance PROTAC permeability and bioactivity and may prove
beneficial to other beyond Ro5 molecules.