Redirecting E3 ubiquitin ligases for targeted protein degradation with heterologous recognition domains.

Targeted protein degradation (TPD) mediated by proteolysis targeting chimeras or molecular glues is an emerging therapeutic strategy. Despite greater than 600 E3 ligases and their associated components, a limited number have been deployed in TPD. Those commonly used include cereblon and von Hippel-Lindau tumor suppressor (VHL), which is expressed widely and for which high affinity ligands are available.

A tetramer of BCL11A is required for stable protein production and fetal hemoglobin silencing.

Down-regulation of BCL11A protein reverses the fetal (HbF, αγ) to adult (HbA, αβ) hemoglobin switch and is exploited in gene-based therapy for hemoglobin disorders. Because of reliance on ex vivo cell manipulation and marrow transplant, such therapies cannot lessen disease burden. To develop new small-molecule approaches, we investigated the state of BCL11A protein in erythroid cells.