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 degron motif, which often comprises
a zinc finger (ZF). These IMiDs, however, also induce the degradation
of endogenous ZF-containing neosubstrates, including IKZF1, IKZF3,
and SALL4. To improve degradation selectivity, we took a bump-and-hole
approach to design and screen bumped IMiD analogues against 8380 ZF
mutants. This yielded a bumped IMiD analogue that induces efficient
degradation of a mutant ZF degron, while not affecting other cellular
proteins, including IKZF1, IKZF3, and SALL4. In proof-of-concept studies,
this system was applied to induce degradation of the optimum degron
fused to CDK9, HPRT1, NanoLuc, or TRIM28. We anticipate that this
system will be a valuable addition to the current arsenal of degron
systems for use in target validation.