TH9619

An MTHFD inhibitor (IC50s = 16, 47, and 47 nM, respectively), inhibits nuclear MTHFD2 and cytoplasmic MTHFD1 but not mitochondrial MTHFD2, leading to an increase in 10-CHO-THF, thymidylate depletion, and cell death, selective for MTHFD1 and MTHFD2 over a panel of 44 kinases at 12 µM, reduces proliferation in a panel of AML cells, impairs DNA replication in HL-60 and THP-1 cells at 50 nM, increases survival in an HL-60 mouse xenograft model at 30 mg/kg twice per day in combination with a low-folate diet. SMILES: NC(NC(N)=NC1=O)=C1CC(NC2=CN=C(C(N[C@H](C(O)=O)CCC(O)=O)=O)C(F)=C2)=O. InChi Code: InChI=1S/C17H18FN7O7/c18-8-3-6(22-10(26)4-7-13(19)24-17(20)25-14(7)29)5-21-12(8)15(30)23-9(16(31)32)1-2-11(27)28/h3,5,9H,1-2,4H2,(H,22,26)(H,23,30)(H,27,28)(H,31,32)(H5,19,20,24,25,29)/t9-/m0/s1. InChi Key: ALGPVOJFIGPPPX-VIFPVBQESA-N