The diversified class of ubiquitin ligases (E3s) provides key specificity factors in the ubiquitin system, selecting substrates for modification and determining the ubiquitin signals to be assembled on them. Consequently, E3s have emerged as attractive targets for specific therapeutic manipulations. While recent advances in developing molecule glue and PROTAC modalities have illustrated the clinical potential of manipulating cullin-RING E3s, progress with E3 inhibitors has been rather slow. In particular, ubiquitin ligases of the HECT class have proven difficult to access with small molecules, despite their defined, catalytic-cysteine dependent active site. In my talk, I will present two examples from our recent work in characterizing and identifying HECT E3-directed small molecule inhibitors:
(i) We discovered that compounds marketed as selective inhibitors of the human HECT E3 HUWE1 rather present substrates of their target ligase, demonstrating exogenous small-molecule ubiquitination in cells. Our findings suggest that the ubiquitin system can be harnessed to transform synthetic compounds into new chemical modalities for basic-science and therapeutic applications.
(ii) We identified a previously uncharacterized, infection-relevant HECT E3 of a eukaryotic pathogen and uncovered the structural basis of its regulation. This mechanism inspires an allosteric small-molecule strategy for blocking the ubiquitination activity of this virulence factor.