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

ABSTRACT: 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

SUBMITTER: Klein VG 

PROVIDER: S-EPMC8713283 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature