Orthogonal IMiD-Degron Pairs Induce Selective Protein Degradation in Cells.

Immunomodulatory imide drugs (IMiDs) including thalidomide, lenalidomide, and pomalidomide, can be used to induce degradation of a protein of interest that is fused to a short zinc finger (ZF) degron motif. These IMiDs, however, also induce degradation of endogenous neosubstrates, including IKZF1 and IKZF3. To improve degradation selectivity, we took a bump-and-hole approach to design and screen bumped IMiD analogs against 8380 ZF mutants. This yielded a bumped IMiD analog that induces efficient degradation of a mutant ZF degron, while not affecting other cellular proteins, including IKZF1 and IKZF3. In proof-of-concept studies, this system was applied to induce efficient degradation of TRIM28, a disease-relevant protein with no known small molecule binders. We anticipate that this system will make a valuable addition to the current arsenal of degron systems for use in target validation.

Using Physicochemical Measurements to Influence Better Compound Design.

During the past decade, the physicochemical quality of molecules under investigation at all stages of the drug discovery process has come under particular scrutiny. The issues associated with excessive lipophilicity and poor solubility in particular are many and varied, ranging from poor outcomes in screening campaigns to promiscuity, limited and/or poorly predictable pharmacokinetic exposure, and, ultimately, greater chances of clinical failure. In this review, contemporary methods to secure key measurements are described along with their relevance to understanding the behavior of molecules in environments pertinent to pharmacological activity. Together, the various measurements contribute to predictive models of both the physicochemical properties themselves and the outcomes they influence.