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Discovering new biology with drug-resistance alleles

Nature Chemical Biology volume 17, pages 1219–1229 (2021)Cite this article

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Abstract

Small molecule drugs form the backbone of modern medicine’s therapeutic arsenal. Often less appreciated is the role that small molecules have had in advancing basic biology. In this Review, we highlight how resistance mutations have unlocked the potential of small molecule chemical probes to discover new biology. We describe key instances in which resistance mutations and related genetic variants yielded foundational biological insight and categorize these examples on the basis of their role in the discovery of novel molecular mechanisms, protein allostery, physiology and cell signaling. Next, we suggest ways in which emerging technologies can be leveraged to systematically introduce and characterize resistance mutations to catalyze basic biology research and drug discovery. By recognizing how resistance mutations have propelled biological discovery, we can better harness new technologies and maximize the potential of small molecules to advance our understanding of biology and improve human health.

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Fig. 1: Resistance mutations identify small molecule targets and reveal new biology.
Fig. 2: Resistance mutations unveil protein structural information and mechanisms of protein allosteric regulation.
Fig. 3: Resistance mutations elucidate physiology and provide insight into species differences in small molecule mechanism of action.
Fig. 4: Allele-selective kinase inhibitors and resistance mutations uncover the importance of BRAF dimerization in the MAPK signaling pathway.
Fig. 5: Resistance mutations uncover the mechanism of action of LSD1 inhibitors in AML.
Fig. 6: Mutagenesis strategies enhance resistance mutation identification and enable novel methods to investigate the small molecule–protein interface.

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Acknowledgements

We thank members of the Liau laboratory, especially A. Siegenfeld, H. S. Kwok, P. Gosavi, N. Lue, S. Roseman, E. M. Garcia and Y. Koga, for discussions and comments on the manuscript. We also thank S. M. Kissler, A. Choudhary, J. Kim, M. D. Shair and D. Kahne for discussions. Figures were created with BioRender.com. A.M.F. was supported by award no. T32GM007753 from the National Institute of General Medical Sciences. This work was supported by award no. 1DP2GM137494 from the National Institute of General Medical Sciences.

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  1. Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, USA

    Allyson M. Freedy & Brian B. Liau

  2. Broad Institute of Harvard and MIT, Cambridge, MA, USA

    Allyson M. Freedy & Brian B. Liau

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Freedy, A.M., Liau, B.B. Discovering new biology with drug-resistance alleles. Nat Chem Biol 17, 1219–1229 (2021). https://doi.org/10.1038/s41589-021-00865-9

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