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Screening candidate anticancer drugs for brain tumor chemotherapy: Pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues

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Summary

A pharmacokinetic [PK]-driven screening process was implemented to select new agents for brain tumor chemotherapy from a series of low molecular weight anticancer agents [ON27x] that consisted of 141 compounds. The screening procedures involved a combination of in silico, in vitro and in vivo mouse studies that were cast into a pipeline of tier 1 and tier 2 failures that resulted in a final investigation of 2 analogues in brain tumor-bearing mice. Tier 1 failures included agents with a molecular weight of > 450 Da, a predicted log P (log P) of either <2 or > 3.5, and a cytotoxicity IC50 value of > 2 uM. Next, 18 compounds underwent cassette dosing studies in normal mice that identified compounds with high systemic clearance, and low blood–brain barrier [BBB] penetration. These indices along with a derived parameter, referred to as the brain exposure index, comprised tier 2 failures that led to the administration of 2 compounds [ON27570, ON27740] as single agents [discrete dosing] to mice bearing intracerebral tumors. Comparison of ON27570’s resultant PK parameters to those obtained in the cassette dosing format suggested a drug-drug interaction most likely at the level of BBB transport, and prompted the use of the in vitro MDCK-MDR1 transport model to help assess the nature of the discrepancy. Overall, the approach was able to identify candidate compounds with suitable PK characteristics yet further revisions to the method, such as the use of in vitro metabolism and transport assays, may improve the PK-directed approach to identify efficacious agents for brain tumor chemotherapy.

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Acknowledgements

This work was supported by grants CA127963 and CA127963-S1 from the NIH.

Conflict of interest

Dr. E.P. Reddy is the scientific founder, stock holder, board member and paid consultant of Onconova Therapeutics Inc. He is also one of the inventors of the patents that describe the compounds described here.

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Authors and Affiliations

  1. Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY, 10029, USA

    Hua Lv, Fan Wang, Qingyu Zhou, Xiaoping Zhang & James M. Gallo

  2. Department of Oncological Sciences, Mount Sinai School of Medicine, New York, NY, 10029, USA

    M. V. Ramana Reddy & E. Premkumar Reddy

  3. Department of Pharmacology and System Therapeutics, Mount Sinai School of Medicine, One Gustave L. Levy Place, Box 1603, New York, NY, 10029, USA

    Hua Lv, Fan Wang & James M. Gallo

Authors
  1. Hua Lv
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  2. Fan Wang
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  3. M. V. Ramana Reddy
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  4. Qingyu Zhou
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  5. Xiaoping Zhang
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  6. E. Premkumar Reddy
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  7. James M. Gallo
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Correspondence to James M. Gallo.

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Lv, H., Wang, F., Reddy, M.V.R. et al. Screening candidate anticancer drugs for brain tumor chemotherapy: Pharmacokinetic-driven approach for a series of (E)-N-(substituted aryl)-3-(substituted phenyl)propenamide analogues. Invest New Drugs 30, 2263–2273 (2012). https://doi.org/10.1007/s10637-012-9806-x

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  • DOI: https://doi.org/10.1007/s10637-012-9806-x

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