Discovery of KT-474a Potent, Selective, and Orally Bioavailable IRAK4 Degrader for the Treatment of Autoimmune Diseases

Interleukin-1 receptor associated kinase 4 (IRAK4) is
an essential
mediator of the IL-1R and TLR signaling pathways, both of which have
been implicated in multiple autoimmune conditions. Hence, blocking
the activity of IRAK4 represents an attractive approach for the treatment
of autoimmune diseases. The activity of this serine/threonine kinase
is dependent on its kinase and scaffolding activities; thus, degradation
represents a potentially superior approach to inhibition. Herein,
we detail the exploration of structure–activity relationships
that ultimately led to the identification of KT-474, a potent, selective,
and orally bioavailable heterobifunctional IRAK4 degrader. This represents
the first heterobifunctional degrader evaluated in a nononcology indication
and dosed to healthy human volunteers. This molecule successfully
completed phase I studies in healthy adult volunteers and patients
with atopic dermatitis or hidradenitis suppurativa. Phase II clinical
trials in both of these indications have been initiated.