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

Adam Bond delivered a talk on the pharmacological and -kinetic effects of amide-to-ester replacements at the pan-selective BET degrader MZ1. The bioisosteric replacement resulted in improved protein degradation through increased permeability of the ester-containing compounds — likely due to masking of solvent-exposed hydrogen bond donors. The ester derivative OMZ1 was 1.5-fold more potent at degrading BRD4 with 10-fold improved permeability by PAMPA than MZ1 but displayed 3-fold weaker binary and ternary affinities to VHL ± BRD4BD2. Furthermore, it formed a less cooperative, ternary complex between VHL and BRD4BD2. Similar trends were also observed for the amide/ester relatives ARV-771 and OARV-771, as well as AB2 and OAB2. In conclusion, degradation of the investigated PROTACs was driven by their ability to enter the cell as the compounds displayed excellent plasma stability.

BioSolveIT DrugSpace 2022 "It's a small world!"
Speaker: Adam Bond (University of Dundee)

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