SHMT inhibitor SHIN2 ((+) SHIN2) is a potent, selective, mammalian SHMT1/2 inhibitor with antileukemic effect in vivo.
(+) SHIN2 blocked proliferation of HCT116 Ras-driven colon cancer cells with IC50 of 300 nM.
(+)SHIN2 inhibited proliferation across various human T-ALL cell lines, and was particularly potent against the human T-ALL cell line Molt4 (IC50=90 nM), a prototypical T-ALL cell line harboring activating mutations in NOTCH1.
(+) SHIN2 (200 mg/kg BID, IP) showed therapeutic activity in mouse primary T-ALL in vivo, significantly decreased tumor burden soon after treatment initiation;
(+)SHIN2 demonstrated synergistic in vivo antileukemic effect with DHFR inhibitor Methotrexate in mouse primary leukemia in Molt3 and Jurkat human T-ALL cell lines, and in human patient-derived T-ALL xenograft.
