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Thalidomide, lenalidomide, and pomalidomide are clinically approved therapies for the treatment of multiple myeloma and other hematologic malignancies. These drugs induce rapid ubiquitination and proteasomal degradation of two transcription factors, Ikaros (IKZF1) and Aiolos (IKZF3), by recruiting them to the CRL4^CRBN E3 ubiquitin ligase through a Cys2-His2 (C2H2) zinc finger (ZF) domain that is present in both proteins and required for their destruction.

Transcription factors have been challenging drug targets because they lack discrete catalytic domains amenable to small-molecule inhibition. Thalidomide analog–induced degradation of IKZF1 and IKZF3 through a C2H2 ZF domain raised the possibility that the >800 C2H2 ZF–containing proteins encoded by the human genome, many of which are putative transcription factors, could be similarly destabilized. We therefore set …