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Integrated pharmacokinetic-driven approach to screen candidate anticancer drugs for brain tumor chemotherapy
Hua Lv1, Xiaoping Zhang, Jyoti Sharma
1Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1603, New York, NY 10029, USA.
Abstract:
The goal of the study was to develop an effective screening strategy to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON123x] by the combined use of in silico, in vitro cytotoxicity, and in vitro ADME profiling studies. The results of these studies were cast into a pipeline of tier 1 and tier 2 procedures that resulted in the identification of ON123300 as the lead compound. Of the 154 ON123xx compounds, 13 met tier 1 screening criteria based on physicochemical properties [i.e., MW < 450 Da, predicted log P between 2 and 3.5] and in vitro glioma cell cytotoxicity [i.e., IC50 < 10 μM] 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.
Insights
Researchers developed a new strategy using computational and laboratory tests to find effective brain tumor chemotherapy drugs. This approach successfully identified a promising lead compound, ON123300, for further development.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Oncology
Background:
- Developing effective chemotherapy agents for brain tumors is challenging due to the blood-brain barrier.
- Existing screening methods may not adequately predict in vivo efficacy for central nervous system targets.
Purpose of the Study:
- To establish an integrated screening strategy for identifying novel low molecular weight anticancer agents for brain tumor chemotherapy.
- To combine in silico, in vitro cytotoxicity, and in vitro ADME profiling to select promising drug candidates.
Main Methods:
- Utilized a tiered approach (Tier 1 and Tier 2) for screening 154 ON123xx compounds.
- Tier 1 involved physicochemical properties and glioma cell cytotoxicity (IC50 < 10 μM).
- Tier 2 assessed metabolic stability, cell permeability, and protein binding, followed by in vivo mouse cassette dosing studies.
Main Results:
- 13 compounds met Tier 1 criteria; 12 proceeded to Tier 2 profiling.
- A strong in vitro/in vivo correlation was observed, with a derived parameter accurately predicting brain drug accumulation (R² = 0.920).
- ON123300 was identified as the lead compound based on the comprehensive screening results.
Conclusions:
- An integrated, pharmacokinetic-driven screening strategy is valuable for identifying potential brain tumor chemotherapy agents.
- The developed in vitro assays effectively predicted in vivo pharmacokinetic behavior and brain penetration.
- This approach facilitates the selection of efficacious agents for challenging brain tumor treatments.
