The development of CNS-active PROTACs is limited by the blood-brain barrier (BBB). This Microperspective briefly reviews BBB physiology and critically evaluates current in silico, in vitro, and in vivo models used to assess brain penetration. These considerations enable a unified analysis of the 30 published 30 CNS-targeted degraders compiled here for the first time, highlighting the lack of a consistent design strategy and offering perspectives for future programs.
BBB-Permeable PROTACs: Where Do We Stand?
Francisco, SerenaFirst
;Apprato, Giulia;Rossi Sebastiano, Matteo;Ermondi, Giuseppe;Caron, Giulia
2026-01-01
Abstract
The development of CNS-active PROTACs is limited by the blood-brain barrier (BBB). This Microperspective briefly reviews BBB physiology and critically evaluates current in silico, in vitro, and in vivo models used to assess brain penetration. These considerations enable a unified analysis of the 30 published 30 CNS-targeted degraders compiled here for the first time, highlighting the lack of a consistent design strategy and offering perspectives for future programs.
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