Replacing the phthalimide core in thalidomide with benzotriazole

Abstract

The advent of proteolysis-targeting chimaeras (PROTACs) mandates that new ligands for the recruitment of E3 ligases are discovered. The traditional immunomodulatory drugs (IMiDs) such as thalidomide and its analogues (all based on the phthalimide glutarimide core) bind to Cereblon, the substrate receptor of the CRL4A^CRBN E3 ligase. We designed a thalidomide analogue in which the phthalimide moiety was replaced with benzotriazole, using an innovative synthesis strategy. Compared to thalidomide, the resulting “benzotriazolo thalidomide” has a similar binding mode, but improved properties, as revealed in crystallographic analyses, affinity assays and cell culture.

Graphical Abstract

Keywords:

• Cereblon
• immunomodulatory drugs
• phthalimide
• benzotriazole
• diazo compounds
• carbene N-H insertion

Acknowledgements

The authors thank the staff of beamline X10SA of the Swiss Light Source (PSI, Villigen, Switzerland) for the excellent technical support. The authors are grateful to the Russian Foundation for Basic Research for financial support (project grant 19–03-00775). The authors thank the Research Center for Magnetic Resonance, the Center for Chemical Analysis and Materials Research, and Research Resource Center for Molecular and Cell Technologies of Saint Petersburg State University Research Park for obtaining the analytical data.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This research was supported by the Russian Foundation for Basic Research (project grant 19–33-90016) and institutional funds of the Max Planck Society.