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The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events

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Abstract

Traditional targets and modalities that have provided rich substrates for medicine design and decades of productive industrial and academic research are not the primary drug discovery engines of the future. There is a steady shift in the target and modality landscape. Novel modalities such as protein degradation are an intense and hot area of research. The explosion of proximity induced ubiquitination of targets and proteasome or lysosome mediated degradation by expropriating E3 ligases (PROTACS, LYTACS) has inspired a number of other proximity induced post-translational modifications such as de-ubiquitination (DUBTACS), phosphorylation (PHICS), de-phosphorylation (PHORCS), acetylation (AceTAGs) to name a few. This review article of emerging TACs (targeting chimeras) provides a sampling of some of the chimeric molecules that preempt these cellular events and highlight opportunities and challenges for prospective medicine design and scientific research.

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Acknowledgements

The authors would like to thank Christoph Zapf and Jodi Muckelbauer for careful review of the manuscript and Isha Verma for helpful discussions and review of figures.

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  1. Bristol Myers Squibb, 700 Bay Road, Redwood City, CA, 94063, USA

    Scott Hollingsworth & Dahlia Weiss

  2. Bristol Myers Squibb, 10300 Campus Point Drive Suite 100, San Diego, CA, 92121, USA

    Scott Johnson, Pouyan Khakbaz & Vera Prytkova

  3. Bristol Myers Squibb, 100 Binney Street, Cambridge, MA, 02142, USA

    Yilin Meng & Olivia Pierce

  4. Bristol Myers Squibb, 200 Cambridge Park Drive, Cambridge, MA, 02140, USA

    Varnavas Mouchlis, Erik Vik & Veerabahu Shanmugasundaram

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  1. Scott Hollingsworth
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Hollingsworth, S., Johnson, S., Khakbaz, P. et al. The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events. Med Chem Res 32, 1294–1314 (2023). https://doi.org/10.1007/s00044-023-03104-z

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