Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios

Immunomodulatory imide drugs (IMiDs), such as thalidomide
and its
analogues, are some of the most commonly utilized E3 ligase ligands
for the development of proteolysis targeting chimeras (PROTACs). While
the canonical neo-substrates of IMiDs (i.e., Ikaros and Aiolos) are
often considered to be unwanted targets of PROTACs, maintaining the
degradation of these neo-substrates also provides the opportunity
to synergistically degrade multiple proteins with a single compound.
Here, we report the development of ALV-07-082-03, a CDK4/CDK6/Helios
triple degrader that consists of palbociclib, an FDA-approved CDK4/6
inhibitor, conjugated to DKY709, a novel IMiD-based Helios degrader.
Pharmacological codegradation of CDK4/6 and Helios resulted in potent
suppression of downstream signaling and proliferation in cancer cells,
as well as enhanced derepression of IL-2 secretion. Thus, not only
do we demonstrate the possibility of rationally redirecting the neo-substrate
specificity of PROTACs by incorporating alternative molecular glue
molecules as E3 ligase ligands but our findings also suggest that
cotargeting CDK4/6 and Helios may have synergistic effects.