Integrated pharmacokinetic-driven approach to screen candidate anticancer drugs for brain tumor chemotherapy
Hua Lv 1, Xiaoping Zhang, Jyoti Sharma, M V Ramana Reddy, E Premkumar Reddy, James M Gallo

The aim of the research ended up being to develop a highly effective screening technique to select new agents for brain tumor chemotherapy from a number of low molecular weight anticancer agents [ON123x] through the combined utilization of in silico, in vitro cytotoxicity, as well as in vitro ADME profiling studies. The outcomes of those studies were cast right into a pipeline of tier 1 and tier 2 procedures that led to the identification of ON123300 because the lead compound. From the 154 ON123xx compounds, 13 met tier 1 screening criteria according to physicochemical qualities [i.e., MW < 450 Da, predicted log P between 2 and 3.5] and in vitro glioma cell cytotoxicity [i.e., IC50 < 10 |¨¬M] and were further tested in tier 2 assays. The tier 2 profiling studies consisted of metabolic stability, MDCK-MDR1 cell permeability and plasma and brain protein binding that were combined to globally assess whether favorable pharmacokinetic properties and brain penetration could be achieved in vivo. In vivo cassette dosing studies were conducted in mice for 12 compounds that permitted examination of in vitro/in vivo relationships that confirmed the suitability of the in vitro assays. A parameter derived from the in vitro assays accurately predicted the extent of drug accumulation in the brain based on the area under the drug concentration-time curve in brain measured in the cassette dosing study (r (2) = 0.920). Overall, the current studies demonstrated the value of an integrated pharmacokinetic-driven approach to identify potentially efficacious agents for brain tumor chemotherapy.