Monoterpenoid fluorophthalimide IMiDs that lack human cereblon binding: synthesis and anti-proliferative, anti-angiogenic and anti-inflammatory activities

Immunomodulatory imide drugs (IMiDs) designed on the backbone of thalidomide are highly effective in the treatment of multiple myeloma (MM). However, acquired resistance ultimately arises and leads to inevitable relapse. A key binding target of IMiDs is cereblon, the substrate recognition element within the E3 ubiquitin ligase complex, which triggers the degradation of neosubstrates that underpin IMiD anticancer and anti-inflammatory actions. A key acquired IMiD resistance mechanism is the down-regulation of cereblon in cancer cells. Introduction of a monoterpenoid group into the thalidomide backbone to replace the classic glutarimide that is involved in cereblon binding resulted in IMiD/monoterpenoid analogues that lack human cereblon binding. Polyfuorination of the phthalimide ring resulted in agents that possessed significant anti-proliferative action against lenalidomide sensitive (MM.1S) and resistant (U266 R10R) MM cells, as well as anti-angiogenesis and anti-inflammatory activities via cereblon-independent mechanisms. From our cellular studies in lenalidomide sensitive and resistant MM cell lines (anti-proliferative assay), human umbilical vein endothelial cells (anti-angiogenesis assay), and RAW 264.7 mouse macrophage cells challenged with lipopolysaccharide (anti-inflammatory assay), we describe four novel lead compounds that warrant further investigation as cereblon-independent IMiDs in cancer and inflammatory disorders.