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Allosteric targeting of receptor tyrosine kinases

Nature Biotechnology volume 32, pages 1113–1120 (2014)Cite this article

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Abstract

The drug discovery landscape has been transformed over the past decade by the discovery of allosteric modulators of all major mammalian receptor superfamilies. Allosteric ligands are a rich potential source of drugs and drug targets with clear therapeutic advantages. G protein–coupled receptors, ligand-gated ion channels and intracellular nuclear hormone receptors have all been targeted by allosteric modulators. More recently, a receptor tyrosine kinase (RTK) has been targeted by an extracellular small-molecule allosteric modulator. Allosteric mechanisms of structurally distinct molecules that target the various receptor families are more alike than originally anticipated and include selectivity, orthosteric probe dependence and pathway-biased signaling.

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Figure 1: All superfamilies of cellular receptors can be allosterically modulated.
Figure 2: Orthosteric versus allosteric receptor mechanisms.
Figure 3: Kinase inhibitors with allosteric properties.
Figure 4: Mechanism of a small-molecule allosteric FGFR inhibitor.
Figure 5: Allosteric targeting strategies for RTKs Schematic representations of RTKs that are targeted by allosteric inhibitors.

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Acknowledgements

F.D.S. is supported by the Fund for Scientific Research (FWO), Flanders. A.C. is a principal research fellow of the National Health and Medical Research Council of Australia. This work is supported by grant #G.0789.11 and #G.00764.10 from the FWO, Belgium; the Belgian Science Policy (IAP #P7/03); Leducq Network of Excellence; and long-term structural Methusalem funding by the Flemish Government to P.C.

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Authors and Affiliations

  1. Department of Cellular and Molecular Medicine, The Switch Laboratory, University of Leuven, Leuven, Belgium

    Frederik De Smet

  2. The Switch Laboratory, Flanders Institute for Biotechnology (VIB), Leuven, Belgium

    Frederik De Smet

  3. Drug Discovery Biology and Department of Pharmacology, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia

    Arthur Christopoulos

  4. Department of Oncology, Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, University of Leuven, Leuven, Belgium

    Peter Carmeliet

  5. Laboratory of Angiogenesis and Neurovascular link, Vesalius Research Center, VIB, Leuven, Belgium

    Peter Carmeliet

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Correspondence to Peter Carmeliet.

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Peter Carmeliet and Frederik De Smet declare to be named as inventors on patent applications, claiming subject matter related to the results described in this paper.

Arthur Christopoulous has no competing interest with regards to this review article.

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De Smet, F., Christopoulos, A. & Carmeliet, P. Allosteric targeting of receptor tyrosine kinases. Nat Biotechnol 32, 1113–1120 (2014). https://doi.org/10.1038/nbt.3028

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