Defining the human C2H2 zinc finger degrome targeted by thalidomide analogs through CRBN.

Science
Authors
Abstract

The small molecules thalidomide, lenalidomide, and pomalidomide induce the ubiquitination and proteasomal degradation of the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) by recruiting a Cys-His (C2H2) zinc finger domain to Cereblon (CRBN), the substrate receptor of the CRL4 E3 ubiquitin ligase. We screened the human C2H2 zinc finger proteome for degradation in the presence of thalidomide analogs, identifying 11 zinc finger degrons. Structural and functional characterization of the C2H2 zinc finger degrons demonstrates how diverse zinc finger domains bind the permissive drug-CRBN interface. Computational zinc finger docking and biochemical analysis predict that more than 150 zinc fingers bind the drug-CRBN complex in vitro, and we show that selective zinc finger degradation can be achieved through compound modifications. Our results provide a rationale for therapeutically targeting transcription factors that were previously considered undruggable.

Year of Publication
2018
Journal
Science
Volume
362
Issue
6414
Date Published
2018 11 02
ISSN
1095-9203
DOI
10.1126/science.aat0572
PubMed ID
30385546
Links
Grant list
R01 HL082941 / HL / NHLBI NIH HHS / United States
P01 CA108631 / CA / NCI NIH HHS / United States
T32 GM007753 / GM / NIGMS NIH HHS / United States
HHMI / Howard Hughes Medical Institute / United States