Biological and Medicinal Chemistry

A Reliable and Sustainable Multicomponent Access to Protein Degraders

Authors

  • Irene Preet Bhela Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale ,
  • Alice Ranza Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale ,
  • Marta Serafini Department of Chemistry, University of Oxford ,
  • Tracey PIRALI Department of Pharmaceutical Sciences, Università degli Studi del Piemonte Orientale

Abstract

The use of small molecules to induce targeted protein degradation is increasingly growing in the drug discovery landscape and protein degraders have progressed rapidly through the pipelines. Despite the advances made so far, their synthesis still represents a significant burden and new approaches are urgently demanded. Herein, we report an unprecedented platform that leverages the modular nature of both multicomponent reactions and degraders to enable the preparation of highly decorated PROTACs and hydrophobic tag-mediated degraders. Compared to the existing methods, our approach offers a versatile and cost-effective means to access libraries of protein degraders and increase the chance of identifying successful clinical candidates.

Version notes

The new version of our paper further explores the versatility of the MCR platform and includes the synthesis of PROTACs displaying an anchor for VHL, the split Ugi reaction performed using aliphatic diamines and other hydrophobic tag-mediated degraders. A scale up of one representative sequence to give 1 gram of final PROTAC is also reported.

Content

Thumbnail image of A Reliable and Sustainable Multicomponent Access to Protein Degraders.pdf

Supplementary material

Thumbnail image of Supplementary Information.pdf
A Reliable and Sustainable Multicomponent Access to Protein Degraders: Supplementary Material
Experimental procedures and spectra data; Copies of 1H and 13C spectra