DDI199 (Contilistat) is a novel multi-target molecule by linking Contilisant and Vorinostat (SAHA), inhibits histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs), and modulate histamine H3 (H3R) and Sigma 1 Receptor (S1R) receptors, shows anti-tumor activity against glioma stem cells (GSCs).
DDI199 inhibits HDAC1 and HDAC5 with IC50 of 0.377 uM and 0.095 uM respectively.
DDI199 does not alter the levels of HDAC6 but promoted a decrease in HDAC1 in U87-MG cells, inhibits MAO-B with IC50 of 14.86 uM, also inhibits both AChE and BChE (Ki=0.87 uM).
DDI199 is cytotoxic for glioma cells and patient-derived stem cells in vitro (IC50<5 uM), also is cytotoxici to other tested tumor cells including gastric, pancreatic and lung cancer cells.
DDI199 deregulates pathways related to cell cycle and neurotransmission in GSCs.
DDI199 (15 mg/kg, i,p, 5 times per week for 4 weeks) reduces GBM , tumorigenicity in vivo, also shows a synergistic effect with TMZ chemotherapy.