Development of a Series of Pyrrolopyridone MAT2A Inhibitors

The
optimization of an allosteric fragment, discovered by differential
scanning fluorimetry, to an in vivo MAT2a tool inhibitor is discussed.
The structure-based drug discovery approach, aided by relative binding
free energy calculations, resulted in AZ’9567 (21), a potent inhibitor in vitro with excellent preclinical pharmacokinetic
properties. This tool showed a selective antiproliferative effect
on methylthioadenosine phosphorylase (MTAP) KO cells, both in vitro
and in vivo, providing further evidence to support the utility of
MAT2a inhibitors as potential anticancer therapies for MTAP-deficient
tumors.