SHMT2 and cancer: Compound 1 is a first-in-class classical antifolatewith a unique spectrum of multitargeted inhibitory activity includingSHMT in mitochondria and de novo purine biosynthesisin the cytosol.36 SHMT2 is a bona fidetumor target with significant impacts on glycine and formate availabilityfor cell proliferation and redox homeostasis.21,34,70 There are compelling arguments for targeting de novo purine biosynthesis for cancer, as antipurine drugsinhibit tumors independent of wild-type p53 status,71 show selectivity based on loss of purine salvage72 and suppress mTOR signaling.73