Development of novel cereblon modulators and their target molecules

Abstract

Thalidomide was developed as a sedative drug during the 1950s. Unfortunately, it has serious teratogenic properties. When pregnant women ingested thalidomide, their infants developed serious malformations such as short limbs. However, thalidomide is now recognized as a clinically useful drug, with several countries approving it as an anti-myeloma treatment. Although the direct target of thalidomide was largely debated until recently, our groups discovered cereblon (CRBN), a substrate receptor of an E3 ubiquitin ligase as a primary target of thalidomide in 2010. CRBN binds not only to thalidomide, but also to various thalidomide derivatives such as lenalidomide and pomalidomide, as well as compounds containing a thalidomide moiety. These compounds are known as cereblon modulators, which induced specific neosubstrates of CRBN E3 ubiquitin ligase such as Ikaros and Aiolos. Several groups have now joined the CRBN research and have reported the basic mechanism of CRBN and its binding compounds. In this review, we present our findings as well as recent advances in this subject area.