Physicochemistry of Cereblon Modulating Drugs Determines Pharmacokinetics and Disposition

Immunomodulatory drugs (IMiDs) thalidomide, lenalidomide, and pomalidomide engage cereblon and mediate a protein interface with neosubstrates such as zinc finger transcription factors promoting their polyubiquitination and degradation. The IMiDs have garnered considerable excitement in drug discovery, leading to exploration of targeted protein degradation strategies. Although the molecular modes-of-action of the IMiDs and related degraders have been the subject of intense research, their pharmacokinetics and disposition have been relatively understudied. Here, we assess the effects of physicochemistry of the IMiDs, the phthalimide EM-12, and the candidate drug CC-220 (iberdomide) on lipophilicity, solubility, metabolism, permeability, intracellular bioavailability, and cell-based potency. The insights yielded in this study will enable the rational property-based design and development of targeted protein degraders in the future.