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Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

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Abstract

In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug–drug interactions. We recently developed methods for high-speed functional screening and quantitative structure–activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

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Acknowledgements

The study performed in the authors’ laboratory was supported, in part, by a research grant entitled “Toxicoproteomics: Expression of ABC transporter genes and drug–drug interactions” (H14-Toxico-002) from the Japanese Ministry of Health and Welfare, a Grant-in-Aid for Creative Scientific Research (no. 13NP0401), and a research grant (No. 14370754) from the Japan Society for the Promotion of Science. The authors thank Drs. Yoji Ikegami and Kazumi Sano (Meiji Pharmaceutical University) as well as Dr. Seigo Sawada (Yakult Central Institute) for their helpful discussion. New SN-analogues were provided from the Yakult Honsha Co., Ltd. (Tokyo, Japan).

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  1. Department of Biomolecular Engineering, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, 4259 Nagatsuta, Midori-ku, Yokohama, 226-8501, Japan

    Toshihisa Ishikawa, Ai Tamura, Hikaru Saito, Kanako Wakabayashi & Hiroshi Nakagawa

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  1. Toshihisa Ishikawa
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  2. Ai Tamura
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  3. Hikaru Saito
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  4. Kanako Wakabayashi
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  5. Hiroshi Nakagawa
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Correspondence to Toshihisa Ishikawa.

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Ishikawa, T., Tamura, A., Saito, H. et al. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design. Naturwissenschaften 92, 451–463 (2005). https://doi.org/10.1007/s00114-005-0019-4

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  • DOI: https://doi.org/10.1007/s00114-005-0019-4

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