Optimization of a Series of RIPK2 PROTACs

Receptor-interacting serine/threonine
protein kinase 2 (RIPK2)
is an important kinase of the innate immune system. Herein, we describe
the optimization of a series of RIPK2 PROTACs which recruit members
of the inhibitor of apoptosis (IAP) family of E3 ligases. Our PROTAC
optimization strategy focused on reducing the lipophilicity of the
early lead which resulted in the identification of analogues with
improved solubility and increased human and rat microsomal stability.
We identified a range of IAP binders that were successfully incorporated
into potent RIPK2 PROTACs with attractive pharmacokinetic profiles.
Compound 20 possessed the best overall profile with good
solubility, potent degradation of RIPK2, and associated inhibition
of TNFα release. A proof-of-concept study utilizing a slow release
matrix demonstrated the feasibility of a long-acting parenteral formulation
with >1 month duration. This represents an attractive alternative
dosing paradigm to oral delivery, especially for chronic diseases
where compliance can be challenging.