Discovery of AK-1690: A Potent and Highly Selective STAT6 PROTAC Degrader

STAT6 is an attractive therapeutic target for human cancers and
other human diseases. Starting from a STAT6 ligand with Ki = 3.5 μM binding affinity, we obtained AK-068
with Ki = 6 nM to STAT6 and at least >85-fold
binding selectivity over STAT5. Using AK-068 and cereblon ligands,
we discovered AK-1690 as the first, potent and selective PROTAC STAT6
degrader. AK-1690 effectively induces degradation of STAT6 protein
in cells with DC50 values of as low as 1 nM while showing
minimal effect on other STAT members up to 10 μM. A single dose
of AK-1690 effectively depletes STAT6 in mouse tissues. Determination
of the first cocrystal structure of STAT6 in complex with AK-1690
provides a structural basis for their interactions. AK-1690 is a powerful
tool with which to investigate the roles of STAT6 in human diseases
and biological processes and a promising lead compound for further
optimization.