Evaluation of linkers and cereblon-directing warheads for the development of orally bioavailable PROTACs

ABSTRACT: PROTACs usually occupy physicochemical space outside the one defined by classical drug-like molecules, which often presents considerable challenges in their optimization and development for oral administration. We have previously reported phenyl glutarimide (PG)-based BET PROTAC SJ995973, with improved overall in vitro degradation and antiproliferative activities compared to its direct thalidomide-based analogue dBET1, but similarly poor in vivo pharmacokinetic profile. Here we describe optimization efforts that led to the discovery of an orally bioavailable PG-PROTAC SJ44236, and results of a comprehensive in vitro/vivo comparative study with direct analogues containing alternative CRBN warheads.

INSTRUMENT(S): Bruker Daltonics instrument model

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Zoran Rankovic  

PROVIDER: MSV000096172 | MassIVE | Wed Oct 23 01:33:00 BST 2024

SECONDARY ACCESSION(S): PXD057094

REPOSITORIES: MassIVE