puc-header

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 Complete

See all articles by Craig Donoghue

Craig Donoghue

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Monica Cubillos-Rojas

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Nuria Gutierrez-Prat

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Carolina Sanchez-Zarzalejo

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Xavier Verdaguer

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Antoni Riera

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Angel R. Nebreda

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona); Catalan Institution of Research and Advanced Studies (ICREA)

More...

Abstract

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

Suggested Citation

Donoghue, Craig and Cubillos-Rojas, Monica and Gutierrez-Prat, Nuria and Sanchez-Zarzalejo, Carolina and Verdaguer, Xavier and Riera, Antoni and Nebreda, Angel R., Optimal Linker Length for Small Molecule PROTACs that Selectively Target P38α and P38β for Degradation (July 3, 2019). CELL-CHEMICAL-BIOLOGY-D-19-00216. Available at SSRN: https://ssrn.com/abstract=3413896 or http://dx.doi.org/10.2139/ssrn.3413896
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Craig Donoghue

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Monica Cubillos-Rojas

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Nuria Gutierrez-Prat

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Carolina Sanchez-Zarzalejo

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Xavier Verdaguer

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Antoni Riera

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona)

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Angel R. Nebreda (Contact Author)

Barcelona Institute of Science and Technology (BIST) - Institute for Research in Biomedicine (IRB Barcelona) ( email )

Parc Científic de Barcelona
C/ Baldiri Reixac 10
Barcelona, 08028
Spain

Catalan Institution of Research and Advanced Studies (ICREA) ( email )

P/ Lluis Companys 23
Barcelona, 08010
Spain

Click here to go to Cell.com

Paper statistics

Abstract Views
495
Downloads
24