Development of BromoTag: A “bump-&-hole”-PROTAC system to induce potent, rapid, and selective degradation of tagged target proteins

Bond, Adam G., Craigon, Conner, Chan, Kwok-Ho, Testa, Andrea, Karapetsas, Athanasios, Fasimoye, Rotimi, Macartney, Thomas, Blow, J. Julian ORCID:, Alessi, Dario R. and Ciulli, Alessio (2021) Development of BromoTag: A “bump-&-hole”-PROTAC system to induce potent, rapid, and selective degradation of tagged target proteins. Journal of Medicinal Chemistry, 64 (20). pp. 15477-15502. ISSN 0022-2623

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Small-molecule-induced protein depletion technologies, also called inducible degrons, allow degradation of genetically engineered target proteins within cells and animals. Here, we design and develop the BromoTag, a new inducible degron system comprising a Brd4 bromodomain L387A variant as a degron tag that allows direct recruitment by heterobifunctional bumped proteolysis targeting chimeras (PROTACs) to hijack the VHL E3 ligase. We describe extensive optimization and structure-activity relationships of our bump-and-hole-PROTACs using a CRISPR knock-in cell line expressing model target BromoTag-Brd2 at endogenous levels. Collectively, our cellular and mechanistic data qualifies bumped PROTAC AGB1 as a potent, fast, and selective degrader of BromoTagged proteins, with a favorable pharmacokinetic profile in mice. The BromoTag adds to the arsenal of chemical genetic degradation tools allowing us to manipulate protein levels to interrogate the biological function and therapeutic potential in cells and in vivo.

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Additional Information: This project has received funding by the European Research Council (ERC, Starting Grant ERC2012-StG-311460 DrugE3CRLs to A.C.); the Innovative Medicines Initiative 2 (IMI2) Joint Undertaking under grant agreement No 875510 (EUbOPEN project to A.C.) from the European Union’s Horizon 2020 research and innovation programme; the Medical Research Council (MRC, MC UU 12016/2 to D.R.A.); and a Wellcome Trust Senior Investigator Award (WT096598MA to J.J.B.). A.G.B. is funded by a PhD studentship from the Medical Research Scotland (MRS) (1170-2017). C.C. is funded by a PhD studentship from the UK Medical Research Council (MRC) under the doctoral training programme in Quantitative and Interdisciplinary approaches to biomedical science (QI Biomed) (MR/N0123735/1). Biophysics and drug discovery activities at Dundee were supported by Welcome Trust strategic awards 100476/Z/12/Z and 094090/Z/10/Z, respectively.
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Depositing User: LivePure Connector
Date Deposited: 10 Jun 2024 14:30
Last Modified: 22 Jul 2024 12:32
DOI: 10.1021/acs.jmedchem.1c01532


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