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Multicomponent therapeutics for networked systems

Nature Reviews Drug Discovery volume 4, pages 71–78 (2005)Cite this article

Key Points

  • The empirical, de novo discovery of multicomponent syncretic drugs requires an integrated informatics and experimental pipeline approach that is dedicated to such a process. Such a method can be used to screen millions of combinations of already approved drugs (or new chemicl entities) for activities in new disease indications55. Scientists at CombinatoRx, Inc. have used this approach to discover numerous syncretic drug candidates that are being tested in early clinical trials (Fig. 5). Such efforts necessarily encompass cross-disciplinary expertise, including mathematics, statistics, physics, chemistry, biology and computer science. With such groups, it is possible to find novel and effective syncretic drugs for a variety of human diseases. Indeed, the systems-based discovery of therapeutics probably represents the next frontier in drug discovery research.

    a | CRx-026 was discovered in a high-throughput combination screen of tens of thousands of combinations of existing drugs for those that synergize in killing human tumour cell lines. CRx-026 is a combination of chlorpromazine, a phenothiazine sedative, and pentamidine, an anti-infective agent. Neither compound is approved for use as an anticancer drug. The colour scale indicates the percentage level of inhibition of viability of A549 lung carcinoma cells by chlorpromazine and pentamidine at a range of concentrations. b | CRx-026 effectively inhibits tumour formation in a nude mouse xenograft model, whereas the individual compounds are by themselves less effective55. The x-axis shows time (in days) post-injection of tumour cells (treatment with compounds begins at 35 days to create a more realistic model of treating existing human tumours). The y-axis shows mean tumour volume (in mm3). Tumour sizes in mice treated with saline vehicle alone (blue line), with 20 mg per kg pentamidine alone (orange line), with 5 mg per kg chlorpromazine (green line) or with both 20 mg per kg pentamidine and 5 mg per kg chlorpromazine (black line) are shown. Only the combination of these two compounds effectively halted tumour growth. Figure reproduced with permission from Ref. 55 © (2003) National Academy of Sciences, USA.

Abstract

Therapeutic regimens that comprise more than one active ingredient are commonly used in clinical medicine. Despite this, most drug discovery efforts search for drugs that are composed of a single chemical entity. A focus in the early drug discovery process on identifying and optimizing the activity of combinations of molecules can result in the identification of more effective drug regimens. A systems perspective facilitates an understanding of the mechanism of action of such drug combinations.

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Figure 1: Networked systems might require multicomponent interventions to modulate signalling outputs.
Figure 2: Response surfaces for combination effect reference models.
Figure 3: The antibiotic Augmentin is a mechanism-based combination drug.
Figure 4: A phenotypic assay for combination screening.

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Acknowledgements

We thank M. Foley for assistance in developing the concepts described here, and J. Lehár, T. Ideker and D. Grau for critical suggestions on this manuscript. B.R.S. is supported in part by a Career Award at the Scientific Interface from the Burroughs Wellcome Fund.

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Authors and Affiliations

  1. Borisy are at CombinatoRx, Inc., 650 Albany Street, Boston, 02118, Massachusetts, USA

    Curtis T. Keith & Alexis A. Borisy

  2. the Department of Biological Sciences and Department of Chemistry, Columbia University, Fairchild Center, MC 2406, 1212 Amsterdam Avenue, New York, 10027, New York, USA

    Brent R. Stockwell

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  1. Curtis T. Keith
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Correspondence to Curtis T. Keith, Alexis A. Borisy or Brent R. Stockwell.

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The authors are employed by, and have equity interests in, CombinatoRx, Inc., a business whose goal is to identify and commercialize novel drug combinations using a systems-based approach.

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Keith, C., Borisy, A. & Stockwell, B. Multicomponent therapeutics for networked systems. Nat Rev Drug Discov 4, 71–78 (2005). https://doi.org/10.1038/nrd1609

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