DHODH inhibitor M62 is a potent, selective dihydroorotate dehydrogenase (DHODH) inhibitor with IC50 of 6.9 nM.
M62 inhibits the proliferation of human CRC cells in vitro with IC50 values ranging from 10.61 to 72.30 nM, HCT116 and HT29 cells are most sensitive (IC50 values of 10.61 and 23.84 nM, respectively).
M62 shows slightly cytotoxicity against human normal colon endothelial cells (NCM460 and HCoEpiC cells IC50 of 238.77 and 263.60 nM, respectively).
M62 induces S phase arrest in CRC cells, modulates multiple gene expression changes in CRC cells, significantly upregulates genes DDB2, DDIT3, GADD45A and TP53, downregulates EIF4B, HSP90AB, and RPS6 gene.
M62 induces the generation of ROS and mitochondrial superoxide, and decreases the production of ΔΨm and ATP, induces DNA damage in CRC cells.
M62 inhibits the expression of DNA repair proteins (ATM, RAD51, BRCA1, and 53BP1) and inhibits the PI3K/AKT/mTOR signaling pathway in CRC cells.
M62 (40 mg/kg, once daily oral gavage) inhibits subcutaneous CRC tumor growth in HCT116 xenograft models.