6‑Amino-3-methylpyrimidinones as Potent, Selective, and Orally Efficacious SHP2 Inhibitors

Protein
tyrosine phosphatase SHP2 is an oncoprotein associated
with cancer as well as a potential immune modulator because of its
role in the programmed cell death PD-L1/PD-1 pathway. In the preceding
manuscript, we described the optimization of a fused, bicyclic screening
hit for potency, selectivity, and physicochemical properties in order
to further expand the chemical diversity of allosteric SHP2 inhibitors.
In this manuscript, we describe the further expansion of our approach,
morphing the fused, bicyclic system into a novel monocyclic pyrimidinone
scaffold through our understanding of SAR and use of structure-based
design. These studies led to the identification of SHP394 (1), an orally efficacious inhibitor of SHP2, with high lipophilic
efficiency, improved potency, and enhanced pharmacokinetic properties.
We also report other pyrimidinone analogues with favorable pharmacokinetic
and potency profiles. Overall, this work improves upon our previously
described allosteric inhibitors and exemplifies and extends the range
of permissible chemical templates that inhibit SHP2 via the allosteric
mechanism.