Allosteric Targeting of the Fanconi Anemia Ubiquitin-Conjugating Enzyme Ube2T by Fragment Screening

Ube2T is the E2 ubiquitin-conjugating
enzyme of the Fanconi anemia
DNA repair pathway and it is overexpressed in several cancers, representing
an attractive target for the development of inhibitors. Despite the
extensive efforts in targeting the ubiquitin system, very few E2 binders
have currently been discovered. Herein we report the identification
of a new allosteric pocket on Ube2T through a fragment screening using
biophysical methods. Several fragments binding to this site inhibit
ubiquitin conjugation in vitro.