Optimal Linker Length for Small Molecule PROTACs that Selectively Target P38α and P38β for Degradation
50 Pages Posted: 3 Jul 2019 Sneak Peek Status: Review CompleteMore...
We report the rational design of hetero-bifunctional small molecules that selectively target p38a and p38b for degradation These proteolysis targeted chimeras (PROTACs) are based on an ATP competitive inhibitor of p38a and p38b, which is linked to thalidomide analogues to recruit the Cereblon E3 ubiquitin ligase complex. Compound synthesis was facilitated by the use of a copper catalyzed “click” reaction. We show that optimization of the linker length and composition is crucial for the degradation-inducing activity of these PROTACs. We provide evidence that these chemical compounds can induce degradation of p38a and p38b but no other related kinases at nanomolar concentrations in several mammalian cell lines. Moreover, we show that the PROTACs mimic the effect of genetic deletion of p38a, and also induce p38a and p38b degradation upon administration to mice. Our compounds contribute to understanding the rational development of PROTACs, and will be a useful tool to validate functions of the p38 MAPK pathway and its involvement in pathologies.
Keywords: Azide-alkyne click reaction, Cereblon, p38 MAPK, PROTAC linker optimization, Protein degradation, Thalidomide derivative
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