Potent inhibitors of human LAT1 (SLC7A5) transporter based on dithiazole and dithiazine compounds for development of anticancer drugs.

摘要: The LAT1 transporter is acknowledged as a pharmacological target of tumours since it strongly overexpressed in many human cancers. purpose this work was to find novel compounds exhibiting potent and prolonged inhibition the transporter. To aim, based on dithiazole dithiazine scaffold have been screened proteoliposome experimental model. Inhibition tested antiport catalysed by hLAT1 transport extraliposomal [3H]histidine exchange with intraliposomal histidine. Out 59 tested, 8 compounds, showing an higher than 90% at 100µM concentration, were subjected dose-response analysis. Two them exhibited IC50 lower 1µM. kinetics, performed two best inhibitors, indicated mixed type respect substrate. Furthermore, still present after removal from reaction mixture, but reversed addition dithioerythritol, S-S reducing agent, indicating formation disulfide(s) between protein. Molecular docking inhibitors homology structural model, highlighted interaction substrate binding site covalent bond residue C407. Indeed, impaired mutant C407A confirming involvement that Cys residue. Treatment SiHa cells expressing relatively high level, most led cell death which not observed treatment compound very poor inhibitory effect.