2. Academic Validation
  3. Optimal linker length for small molecule PROTACs that selectively target p38α and p38β for degradation

Optimal linker length for small molecule PROTACs that selectively target p38α and p38β for degradation

  • Eur J Med Chem. 2020 Sep 1:201:112451. doi: 10.1016/j.ejmech.2020.112451.
Craig Donoghue 1,  Monica Cubillos-Rojas 1,  Nuria Gutierrez-Prat 1,  Carolina Sanchez-Zarzalejo 1,  Xavier Verdaguer 2,  Antoni Riera 3,  Angel R Nebreda 4
Affiliations

Affiliations

  • 1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain.
  • 2 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain; Dept. Química Inorgànica i Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain.
  • 3 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain; Dept. Química Inorgànica i Orgànica, Universitat de Barcelona, Martí i Franquès 1, 08028, Barcelona, Spain. Electronic address: [email protected].
  • 4 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Baldiri Reixac 10, 08028, Barcelona, Spain; ICREA, Pg. Lluís Companys 23, 08010, Barcelona, Spain. Electronic address: [email protected].
PMID: 32634680 DOI: 10.1016/j.ejmech.2020.112451
Abstract

We report the design of hetero-bifunctional small molecules that selectively target p38α and p38β for degradation. These proteolysis targeted chimeras (PROTACs) are based on an ATP competitive inhibitor of p38α and p38β, 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 p38α and p38β but no other related kinases at nanomolar concentrations in several mammalian cell lines. Accordingly, the PROTACs inhibit stress and cytokine-induced p38α signaling. Our compounds contribute to understanding the development of PROTACs, and provide a useful tool to investigate functions of the p38 MAPK pathway and its involvement in diseases.

Keywords

Azide-alkyne click reaction; Cereblon; PROTAC linker optimization; Protein degradation; Thalidomide derivative; p38 MAPK.

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