MDH1/2-IN-1 is an MDH1/2 inhibitor with IC50 values of 1.07 nM and 1.06 nM, respectively. It suppresses mitochondrial respiration and the HIF-1α pathway. MDH1/2-IN-1 exhibits significant antitumor potential and offers new avenues for developing drugs targeting cancer metabolism.

MDH1/2-IN-1 (Compound 16c) effectively suppresses the activity of human recombinant MDH1 (IC 50: 1.07 nM) and MDH2 (IC 50: 1.06 nM) at concentrations of 60-300 μM over a period of 0.5 hours. At concentrations of 0.1-10 μM for 12-24 hours, MDH1/2-IN-1 inhibits the hypoxia-induced accumulation of HIF-1α in a dose-dependent manner in human colon cancer HCT116 cells. Additionally, at concentrations of 5-20 μM, it suppresses the expression of HIF-1α target genes, such as VEGF, GLUT1, and pyruvate dehydrogenase kinase 1 (PDK1), without affecting HIF-1α mRNA levels. Furthermore, MDH1/2-IN-1 at 1.25-10 μM significantly reduces oxygen consumption rate (OCR) in HCT116 cells, inhibiting mitochondrial respiration and thereby decreasing ATP production.

MDH1/2-IN-1, administered intraperitoneally at a dosage of 20 mg/kg once daily for 14 days, reduced tumor growth by 63.4% in the HCT116 colon cancer xenograft model, with no significant toxicity observed.