Abstract
Combinatorial control of biological processes, in which redundancy and multifunctionality are the norm, fundamentally limits the therapeutic index that can be achieved by even the most potent and highly selective drugs. Thus, it will almost certainly be necessary to use new 'targeted' pharmaceuticals in combinations. Multicomponent drugs are standard in cytotoxic chemotherapy, but their development has required arduous empirical testing. However, experimentally validated numerical models should greatly aid in the formulation of new combination therapies, particularly those tailored to the needs of specific patients. This perspective focuses on opportunities and challenges inherent in the application of mathematical modeling and systems approaches to pharmacology, specifically with respect to the idea of achieving combinatorial selectivity through use of multicomponent drugs.
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Acknowledgements
We thank B. Harms for helpful suggestions and comments on the manuscript. This work was supported by National Institutes of Health grant GM68762 and by Merrimack Pharmaceuticals.
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P.K.S. is a co-founder of Merrimack Pharmaceuticals and chair of the Scientific Advisory Board.
Supplementary information
Supplementary Table 1
Species, parameters and reactions that can be used to recreate the mechanistic models for Figure 2 (two ligands, two inhibitors). (PDF 235 kb)
Supplementary Table 2
Species, parameters and reactions that can be used to recreate the mechanistic models for Figure 3 (exclusive versus nonexclusive), Figure 4 (linear and ultrasensitive), Figure 5 (negative feedback) and Figure 6 (diseased linear and ultrasensitive). (PDF 239 kb)
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Fitzgerald, J., Schoeberl, B., Nielsen, U. et al. Systems biology and combination therapy in the quest for clinical efficacy. Nat Chem Biol 2, 458–466 (2006). https://doi.org/10.1038/nchembio817
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DOI: https://doi.org/10.1038/nchembio817
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