Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Unifying principles of bifunctional, proximity-inducing small molecules

Abstract

Nature uses a variety of tools to mediate the flow of information in cells, many of which control distances between key biomacromolecules. Researchers have thus generated compounds whose activities stem from interactions with two (or more) proteins simultaneously. In this Perspective, we describe how these ‘bifunctional’ small molecules facilitate the study of an increasingly wide range of complex biological phenomena and enable the drugging of otherwise challenging therapeutic targets and processes. Despite their structural and functional differences, all bifunctional molecules employ Nature’s strategy of altering interactomes and inducing proximity to modulate biology. They therefore exhibit a shared set of chemical and biophysical principles that have not yet been appreciated fully. By highlighting these commonalities—and their wide-ranging consequences—we hope to chip away at the artificial barriers that threaten to constrain this interdisciplinary field. Doing so promises to yield remarkable benefits for biological research and therapeutics discovery.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Bifunctional compounds can be grouped into two classes: with and without linkers.
Fig. 2: Scaffold proteins leverage the physical organic chemistry principle of effective molarity to accelerate enzymatic reactions.
Fig. 3: X-ray crystallography data reveal common mechanistic principles of molecular glues.
Fig. 4: Bifunctional natural products exhibit a wide range of structural complexity.
Fig. 5: Bifunctional compounds exhibit a variety of biological activities.
Fig. 6: Triads of bifunctional molecules with differing sets of structural features but shared biological activities.

References

  1. 1.

    Rakhit, R., Navarro, R. & Wandless, T. J. Chemical biology strategies for posttranslational control of protein function. Chem. Biol. 21, 1238–1252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Kraft, A. S. & Anderson, W. B. Phorbol esters increase the amount of Ca2+, phospholipid-dependent protein kinase associated with plasma membrane. Nature 301, 621–623 (1983).

    Article  CAS  Google Scholar 

  3. 3.

    Rando, R. R. & Kishi, Y. Structural basis of protein kinase C activation by diacylglycerols and tumor promoters. Biochemistry 31, 2211–2218 (1992).

    Article  CAS  Google Scholar 

  4. 4.

    Wender, P. A. et al. Modeling of the bryostatins to the phorbol ester pharmacophore on protein kinase C. Proc. Natl. Acad. Sci. USA 85, 7197–7201 (1988).

    Article  CAS  Google Scholar 

  5. 5.

    Che, Y., Gilbert, A. M., Shanmugasundaram, V. & Noe, M. C. Inducing protein-protein interactions with molecular glues. Bioorg. Med. Chem. Lett. 28, 2585–2592 (2018).

    Article  CAS  Google Scholar 

  6. 6.

    Winter, G. E. et al. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science 348, 1376–1381 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Bondeson, D. P. et al. Catalytic in vivo protein knockdown by small-molecule PROTACs. Nat. Chem. Biol. 11, 611–617 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. 9.

    Schreiber, S. L. & Crabtree, G. R. The mechanism of action of cyclosporin A and FK506. Immunol. Today 13, 136–142 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Sabers, C. J. et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J. Biol. Chem. 270, 815–822 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Austin, D. J., Crabtree, G. R. & Schreiber, S. L. Proximity versus allostery: the role of regulated protein dimerization in biology. Chem. Biol. 1, 131–136 (1994). This paper contrasts the concept of induced proximity to that of the general phenomenon of allosteric regulation. The authors propose that induced co-localization of proteins via synthetic ‘dimerizers’ may be sufficient to study a variety of biological systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Stanton, B. Z., Chory, E. J. & Crabtree, G. R. Chemically induced proximity in biology and medicine. Science 359, eaao5902 (2018). This Review discusses the breadth of biological systems that have been studied with molecular glues known as chemical inducers of proximity (CIPs), primarily focusing on cases involving protein engineering.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ellis, R. J. & Minton, A. P. Cell biology: join the crowd. Nature 425, 27–28 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Page, M. I. & Jencks, W. P. Entropic contributions to rate accelerations in enzymic and intramolecular reactions and the chelate effect. Proc. Natl. Acad. Sci. USA 68, 1678–1683 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. 15.

    Kirby, A.J. in Advances in Physical Organic Chemistry (eds. Gold, V. & Bethell, D.) 17, 183–278 (Academic Press, 1980).

  16. 16.

    Tenud, L., Farooq, S., Seibl, J., Eschenmoser, A. & Endocyclische, S. N. Reaktionen am gesättigten Kohlenstoff? Vorläufige Mitteilung. Helv. Chim. Acta 53, 2059–2069 (1970). This paper describes a nucleophilic substitution reaction in which the intramolecular pathway that proceeds via an endocyclic transition state is disfavored. In doing so, it reveals that increasing the proximity of reactive species is not always sufficient to achieve rate acceleration.

    Article  CAS  Google Scholar 

  17. 17.

    Baldwin, J. E. Rules for ring closure. J. Chem. Soc. Chem. Commun. 1976, 734–736 (1976).

    Article  Google Scholar 

  18. 18.

    Good, M. C., Zalatan, J. G. & Lim, W. A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680–686 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. 19.

    Shaw, A. S. & Filbert, E. L. Scaffold proteins and immune-cell signalling. Nat. Rev. Immunol. 9, 47–56 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Choi, K. Y., Satterberg, B., Lyons, D. M. & Elion, E. A. Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78, 499–512 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Alberti, S. Phase separation in biology. Curr. Biol. 27, R1097–R1102 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Whyte, W. A. et al. Master transcription factors and mediator establish super-enhancers at key cell identity genes. Cell 153, 307–319 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Hnisz, D., Shrinivas, K., Young, R. A., Chakraborty, A. K. & Sharp, P. A. A phase separation model for transcriptional control. Cell 169, 13–23 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Sabari, B. R. et al. Coactivator condensation at super-enhancers links phase separation and gene control. Science 361, eaar3958 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Yang, H. et al. mTOR kinase structure, mechanism and regulation. Nature 497, 217–223 (2013). This paper describes several X-ray crystal structures of mTOR complexed with various regulatory small molecules and protein binding partners. Analysis of these structures reveals that rapamycin–FKBP12 inhibits mTOR by physically blocking substrates from accessing its active site.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Gadd, M. S. et al. Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 13, 514–521 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Kopytek, S. J., Standaert, R. F., Dyer, J. C. & Hu, J. C. Chemically induced dimerization of dihydrofolate reductase by a homobifunctional dimer of methotrexate. Chem. Biol. 7, 313–321 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Petzold, G., Fischer, E. S. & Thomä, N. H. Structural basis of lenalidomide-induced CK1α degradation by the CRL4(CRBN) ubiquitin ligase. Nature 532, 127–130 (2016). This paper examines the structural underpinnings of lenalidomide’s ability to alter the substrate specificity of the E3 ubiquitin ligase cereblon (CRBN).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Woodward, A. W. & Bartel, B. Auxin: regulation, action, and interaction. Ann. Bot. 95, 707–735 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Chini, A. et al. The JAZ family of repressors is the missing link in jasmonate signalling. Nature 448, 666–671 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Nishimura, N. et al. Structural mechanism of abscisic acid binding and signaling by dimeric PYR1. Science 326, 1373–1379 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Brown, E. J. et al. A mammalian protein targeted by G1-arresting rapamycin-receptor complex. Nature 369, 756–758 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Liu, J. et al. Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes. Cell 66, 807–815 (1991). This paper identifies calcineurin as the shared target of cyclosporin A (complexed with cyclophilin) and FK506 (complexed with FKBP12). It also shows that the rapamycin–FKBP12 complex, cyclophilin alone, and FKBP12 alone do not inhibit calcineurin.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Pua, K. H., Stiles, D. T., Sowa, M. E. & Verdine, G. L. IMPDH2 is an intracellular target of the cyclophilin A and sanglifehrin A complex. Cell Reports 18, 432–442 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Schreiber, S. L. A chemical biology view of bioactive small molecules and a binder-based approach to connect biology to precision medicines. Isr. J. Chem. 59, 52–59 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. 36.

    Crabtree, G. R. & Schreiber, S. L. Three-part inventions: intracellular signaling and induced proximity. Trends Biochem. Sci. 21, 418–422 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 37.

    Diver, S. T. & Schreiber, S. L. Single-step synthesis of cell-permeable protein dimerizers that activate signal transduction and gene expression. J. Am. Chem. Soc. 119, 5106–5109 (1997).

    Article  CAS  Google Scholar 

  38. 38.

    Pruschy, M. N. et al. Mechanistic studies of a signaling pathway activated by the organic dimerizer FK1012. Chem. Biol. 1, 163–172 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Belshaw, P. J., Ho, S. N., Crabtree, G. R. & Schreiber, S. L. Controlling protein association and subcellular localization with a synthetic ligand that induces heterodimerization of proteins. Proc. Natl. Acad. Sci. USA 93, 4604–4607 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Wehr, M. C. et al. Monitoring regulated protein-protein interactions using split TEV. Nat. Methods 3, 985–993 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Gray, D. C., Mahrus, S. & Wells, J. A. Activation of specific apoptotic caspases with an engineered small-molecule-activated protease. Cell 142, 637–646 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zetsche, B., Volz, S. E. & Zhang, F. A split-Cas9 architecture for inducible genome editing and transcription modulation. Nat. Biotechnol. 33, 139–142 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Liberles, S. D., Diver, S. T., Austin, D. J. & Schreiber, S. L. Inducible gene expression and protein translocation using nontoxic ligands identified by a mammalian three-hybrid screen. Proc. Natl. Acad. Sci. USA 94, 7825–7830 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011). This paper demonstrates the ability of a molecular glue to induce the activity of engineered caspase 9 in stem cell transplant patients. In doing so, it establishes that bifunctional-compound-induced proximity of fusion proteins can have therapeutic benefits in the clinic.

    Article  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Cyrus, K. et al. Jostling for position: optimizing linker location in the design of estrogen receptor-targeting PROTACs. ChemMedChem 5, 979–985 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Krishnamurthy, V. M., Semetey, V., Bracher, P. J., Shen, N. & Whitesides, G. M. Dependence of effective molarity on linker length for an intramolecular protein-ligand system. J. Am. Chem. Soc. 129, 1312–1320 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Douglass, E. F. Jr., Miller, C. J., Sparer, G., Shapiro, H. & Spiegel, D. A. A comprehensive mathematical model for three-body binding equilibria. J. Am. Chem. Soc. 135, 6092–6099 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Lai, A. C. & Crews, C. M. Induced protein degradation: an emerging drug discovery paradigm. Nat. Rev. Drug Discov. 16, 101–114 (2017). This Review summarizes several small-molecule-based approaches for targeted protein degradation, such as PROTACs, hydrophobic tagging (HyT), and selective hormone receptor degraders (e.g., SERDs).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Chamberlain, P. P. & Hamann, L. G. Development of targeted protein degradation therapeutics. Nat. Chem. Biol. 15, 937–944 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Dikic, I. Proteasomal and autophagic degradation systems. Annu. Rev. Biochem. 86, 193–224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Sakamoto, K. M. et al. Protacs: chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation. Proc. Natl. Acad. Sci. USA 98, 8554–8559 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Silva, M. C. et al. Targeted degradation of aberrant tau in frontotemporal dementia patient-derived neuronal cell models. eLife 8, e45457 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  53. 53.

    Pfaff, P., Samarasinghe, K. T. G., Crews, C. M. & Carreira, E. M. Reversible spatiotemporal control of induced protein degradation by bistable photoPROTACs. ACS Cent. Sci. 5, 1682–1690 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Reynders, M. et al. PHOTACs enable optical control of protein degradation. Preprint at ChemRxiv https://doi.org/10.26434/chemrxiv.8206688.v2 (2019).

  55. 55.

    Neklesa, T. K. et al. Small-molecule hydrophobic tagging-induced degradation of HaloTag fusion proteins. Nat. Chem. Biol. 7, 538–543 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Long, M. J. C., Gollapalli, D. R. & Hedstrom, L. Inhibitor mediated protein degradation. Chem. Biol. 19, 629–637 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Banik, S., Pedram, K., Wisnovsky, S., Riley, N. & Bertozzi, C. Lysosome targeting chimeras (LYTACs) for the degradation of secreted and membrane proteins. Preprint at ChemRxiv https://doi.org/10.26434/chemrxiv.7927061 (2019).

  58. 58.

    Schellenberg, G. D. & Montine, T. J. The genetics and neuropathology of Alzheimer’s disease. Acta Neuropathol. 124, 305–323 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Gestwicki, J. E., Crabtree, G. R. & Graef, I. A. Harnessing chaperones to generate small-molecule inhibitors of amyloid beta aggregation. Science 306, 865–869 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Zhang, Z. & Shokat, K. M. Bifunctional small-molecule ligands of K-Ras induce its association with immunophilin proteins. Angew. Chem. Int. Ed. Engl. 58, 16314–16319 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503, 548–551 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Koppel, G. A. Recent advances with monoclonal antibody drug targeting for the treatment of human cancer. Bioconjug. Chem. 1, 13–23 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Shokat, K. M. & Schultz, P. G. Redirecting the immune response: ligand-mediated immunogenicity. J. Am. Chem. Soc. 113, 1861–1862 (1991).

    Article  CAS  Google Scholar 

  64. 64.

    Bertozzi, C. & Bednarski, M. C-glycosyl compounds bind to receptors on the surface of Escherichia coli and can target proteins to the organism. Carbohydr. Res. 223, 243–253 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Owen, R. M. et al. Bifunctional ligands that target cells displaying the α v β3 integrin. ChemBioChem 8, 68–82 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Danhier, F., Le Breton, A. & Préat, V. RGD-based strategies to target alpha(v) beta(3) integrin in cancer therapy and diagnosis. Mol. Pharm. 9, 2961–2973 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Carlson, C. B., Mowery, P., Owen, R. M., Dykhuizen, E. C. & Kiessling, L. L. Selective tumor cell targeting using low-affinity, multivalent interactions. ACS Chem. Biol. 2, 119–127 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Parker, C. G., Domaoal, R. A., Anderson, K. S. & Spiegel, D. A. An antibody-recruiting small molecule that targets HIV gp120. J. Am. Chem. Soc. 131, 16392–16394 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Rullo, A. F. et al. Re-engineering the immune response to metastatic cancer: antibody-recruiting small molecules targeting the urokinase receptor. Angew. Chem. Int. Ed. Engl. 55, 3642–3646 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Jones, C. N. et al. Bifunctional small molecules enhance neutrophil activities against Aspergillus fumigatus in vivo and in vitro. Front. Immunol. 10, 644 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    McEnaney, P. J., Parker, C. G., Zhang, A. X. & Spiegel, D. A. Antibody-recruiting molecules: an emerging paradigm for engaging immune function in treating human disease. ACS Chem. Biol. 7, 1139–1151 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Adelman, K. & Lis, J. T. Promoter-proximal pausing of RNA polymerase II: emerging roles in metazoans. Nat. Rev. Genet. 13, 720–731 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 73.

    Erwin, G. S. et al. Synthetic transcription elongation factors license transcription across repressive chromatin. Science 358, 1617–1622 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Jordan, M. A. & Wilson, L. Microtubules and actin filaments: dynamic targets for cancer chemotherapy. Curr. Opin. Cell Biol. 10, 123–130 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Haggarty, S. J. et al. Dissecting cellular processes using small molecules: identification of colchicine-like, taxol-like and other small molecules that perturb mitosis. Chem. Biol. 7, 275–286 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Ceccarelli, D. F. et al. An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme. Cell 145, 1075–1087 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Huang, H. et al. E2 enzyme inhibition by stabilization of a low-affinity interface with ubiquitin. Nat. Chem. Biol. 10, 156–163 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. 78.

    Struntz, N. B. et al. Stabilization of the Max homodimer with a small molecule attenuates Myc-driven transcription. Cell. Chem. Biol. 26, 711–723.e14 (2019).

    CAS  Google Scholar 

  79. 79.

    Sijbesma, E. et al. Site-directed fragment-based screening for the discovery of protein-protein interaction stabilizers. J. Am. Chem. Soc. 141, 3524–3531 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Long, X. & Nephew, K. P. Fulvestrant (ICI 182,780)-dependent interacting proteins mediate immobilization and degradation of estrogen receptor-α. J. Biol. Chem. 281, 9607–9615 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Blake, R. A. Abstract 4452: GNE-0011, a novel monovalent BRD4 degrader. Cancer Res. 79, 4452 (2019).

    Google Scholar 

  82. 82.

    Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. 83.

    Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 49–53 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Han, T. et al. Anticancer sulfonamides target splicing by inducing RBM39 degradation via recruitment to DCAF15. Science 356, eaal3755 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Uehara, T. et al. Selective degradation of splicing factor CAPERα by anticancer sulfonamides. Nat. Chem. Biol. 13, 675–680 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. 86.

    Li, Z. et al. Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds. Nature 575, 203–209 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    de Waal, L. et al. Identification of cancer-cytotoxic modulators of PDE3A by predictive chemogenomics. Nat. Chem. Biol. 12, 102–108 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. 88.

    Guo, Z. et al. Rapamycin-inspired macrocycles with new target specificity. Nat. Chem. 11, 254–263 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Bierer, B. E., Somers, P. K., Wandless, T. J., Burakoff, S. J. & Schreiber, S. L. Probing immunosuppressant action with a nonnatural immunophilin ligand. Science 250, 556–559 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. 90.

    Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 91.

    McGrath, J. P. et al. Pharmacological inhibition of the histone lysine demethylase KDM1A suppresses the growth of multiple acute myeloid leukemia subtypes. Cancer Res. 76, 1975–1988 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. 92.

    Ishikawa, Y. et al. A novel LSD1 inhibitor T-3775440 disrupts GFI1B-containing complex leading to transdifferentiation and impaired growth of AML cells. Mol. Cancer Ther. 16, 273–284 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Maiques-Diaz, A. et al. Enhancer activation by pharmacologic displacement of LSD1 from GFI1 induces differentiation in acute myeloid leukemia. Cell Rep. 22, 3641–3659 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Vinyard, M. E. et al. CRISPR-suppressor scanning reveals a nonenzymatic role of LSD1 in AML. Nat. Chem. Biol. 15, 529–539 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. 95.

    Polier, S. et al. ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat. Chem. Biol. 9, 307–312 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. 96.

    Jones, L. H. Small-molecule kinase downregulators. Cell Chem. Biol. 25, 30–35 (2018). This Review covers small-molecule-based methods to decrease levels of kinases in cells, particularly in the context of cancer. Both linker-containing molecules (e.g., PROTACs) and non-linker compounds are discussed, including several FDA-approved, ATP-competitive compounds (e.g., erlotinib and vemurafenib).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Garcia-Seisdedos, H., Empereur-Mot, C., Elad, N. & Levy, E. D. Proteins evolve on the edge of supramolecular self-assembly. Nature 548, 244–247 (2017). This paper studies the phenomenon by which proteins self-assemble into symmetric multimeric complexes. The authors often observed that a single point mutation was sufficient to catalyze polymerization, which suggests that proteins are primed for self-assembly.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Zimmermann, G. & Neri, D. DNA-encoded chemical libraries: foundations and applications in lead discovery. Drug Discov. Today 21, 1828–1834 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Parker, C. G. et al. Ligand and target discovery by fragment-based screening in human cells. Cell 168, 527–541.e29 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank B. Melillo, J. Ostrem, and B. Wagner for their critical feedback on the manuscript. Research from the Schreiber laboratory in the area covered by this Perspective was generously supposed by the National Institute of General Medical Sciences.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Stuart L. Schreiber.

Ethics declarations

Competing interests

S.L.S. serves on the Board of Directors of the Genomics Institute of the Novartis Research Foundation (“GNF”); is a shareholder and serves on the Board of Directors of Jnana Therapeutics; is a shareholder of Forma Therapeutics; is a shareholder and advises Decibel Therapeutics and Eikonizo Therapeutics; serves on the Scientific Advisory Boards of Eisai Co., Ltd., Ono Pharma Foundation, Exo Therapeutics, and F-Prime Capital Partners; and is a Novartis Faculty Scholar. C.J.G. is an employee of Vertex Pharmaceuticals.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Gerry, C.J., Schreiber, S.L. Unifying principles of bifunctional, proximity-inducing small molecules. Nat Chem Biol 16, 369–378 (2020). https://doi.org/10.1038/s41589-020-0469-1

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing