The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs
Open accessAbstract
Off-target effects are persistent issues of modern inhibition-based therapies. By merging the strategies of photopharmacology and small molecule degraders, we introduce a novel concept for persistent spatiotemporal control of induced protein degradation that potentially prevents off-target toxicity. Building on the successful principle of bifunctional all-small molecule Proteolysis Targeting Chimeras (PROTACs), we designed photoswitchable PROTACs ( photoPROTACs ) by including ortho- F 4 -azobenzene linkers between both warhead ligands. This highly bistable yet photoswitchable structural component leads to reversible control over the topological distance between both ligands. The azo - cis -isomer is observed to be inactive because the distance defined by the linker is prohibitively short to permit complex formation between the protein binding partners. By contrast, the azo - trans -isomer is active because it can engage both protein partners to form the necessary and productive ternary complex. Importantly, due to the bistable nature of the ortho -F 4 -azobenzene moiety employed, the photostationary state of the photoPROTAC is persistent, with no need for continuous irradiation. This technique offers reversible on/off switching of protein degradation that is compatible with an intracellular environment and, therefore, could be vastly useful in experimental probing of biological signaling pathways – especially those crucial for oncogenic signal transduction. Additionally, this strategy may be suitable for therapeutic implementation in a wide variety of disease phenotypes. By enabling reversible activation and deactivation of protein degradation, photoPROTACs offer advantages over conventional photocaging strategies that irreversibly release active agents.
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Cites
Oncogenic Signaling Pathways in The Cancer Genome Atlas
Sanchez-Vega, F., Mina, M., Armenia, J., Chatila, W. K., Luna, A., La, K. C., Dimitriadoy, S., Liu, D. L., Kantheti, H. S., Saghafinia, S., et al. (2018) · Cell · doi:10.1016/j.cell.2018.03.035 · Cited by 3,201
Phthalimide conjugation as a strategy for in vivo target protein degradation
Winter, G. E., Buckley, D. L., Paulk, J., Roberts, J. M., Souza, A., Dhe-Paganon, S., & Bradner, J. E. (2015) · Science · doi:10.1126/science.aab1433 · Cited by 1,760
Catalytic in vivo protein knockdown by small-molecule PROTACs
Bondeson, D. P., Mares, A., Smith, I. E. D., Ko, E., Campos, S., Miah, A. H., Mulholland, K. E., Routly, N., Buckley, D. L., Gustafson, J. L., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1858 · Cited by 1,356
Self-citationLessons in PROTAC Design from Selective Degradation with a Promiscuous Warhead
Bondeson, D. P., Smith, B. E., Burslem, G. M., Buhimschi, A. D., Hines, J., Jaime-Figueroa, S., Wang, J., Hamman, B. D., Ishchenko, A., & Crews, C. M. (2018) · Cell Chemical Biology · doi:10.1016/j.chembiol.2017.09.010 · Cited by 923
Self-citationPROTAC-induced BET protein degradation as a therapy for castration-resistant prostate cancer
Raina, K., Lu, J., Qian, Y., Altieri, M., Gordon, D., Rossi, A. M. K., Wang, J., Chen, X., Dong, H., Siu, K., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521738113 · Cited by 852
Self-citationPharmacological perturbation of CDK9 using selective CDK9 inhibition or degradation
Olson, C. M., Jiang, B., Erb, M. A., Liang, Y., Doctor, Z. M., Zhang, Z., Zhang, T., Kwiatkowski, N., Boukhali, M., Green, J. L., et al. (2018) · Nature Chemical Biology · doi:10.1038/nchembio.2538 · Cited by 552
Differential PROTAC substrate specificity dictated by orientation of recruited E3 ligase
Smith, B. E., Wang, S. L., Jaime-Figueroa, S., Harbin, A., Wang, J., Hamman, B. D., & Crews, C. M. (2019) · Nature Communications · doi:10.1038/s41467-018-08027-7 · Cited by 517
Self-citationBuhimschi, A. D., Armstrong, H. A., Toure, M., Jaime-Figueroa, S., Chen, T. L., Lehman, A. M., Woyach, J. A., Johnson, A. J., Byrd, J. C., & Crews, C. M. (2018) · Biochemistry · doi:10.1021/acs.biochem.8b00391 · Cited by 394
Self-citationFunctional TRIM24 degrader via conjugation of ineffectual bromodomain and VHL ligands
Gechijian, L. N., Buckley, D. L., Lawlor, M. A., Reyes, J. M., Paulk, J., Ott, C. J., Winter, G. E., Erb, M. A., Scott, T. G., Xu, M., et al. (2018) · Nature Chemical Biology · doi:10.1038/s41589-018-0010-y · Cited by 222
Cited by
PROTACs: past, present and future
Li, K., & Crews, C. M. (2022) · Chemical Society Reviews · doi:10.1039/d2cs00193d · Cited by 869
Self-citationAdvancing targeted protein degradation for cancer therapy
Dale, B., Cheng, M., Park, K.-S., Kaniskan, H. Ü., Xiong, Y., & Jin, J. (2021) · Nature Reviews Cancer · doi:10.1038/s41568-021-00365-x · Cited by 632
PROTACs: great opportunities for academia and industry
Sun, X., Gao, H., Yang, Y., He, M., Wu, Y., Song, Y., Tong, Y., & Rao, Y. (2019) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-019-0101-6 · Cited by 613
Proteolysis-targeting chimera (PROTAC) for targeted protein degradation and cancer therapy
Li, X., & Song, Y. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00885-3 · Cited by 521
PROTACs: An Emerging Therapeutic Modality in Precision Medicine
Nalawansha, D. A., & Crews, C. M. (2020) · Cell Chemical Biology · doi:10.1016/j.chembiol.2020.07.020 · Cited by 490
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Metadata
- Authors
- Pfaff, P., Samarasinghe, K. T. G., Crews, C. M., & Carreira, E. M.
- Venue
- ACS Central Science
- Publisher
- American Chemical Society (ACS)
- Published
- 2019-09-17
- Volume
- 5
- Issue
- 10
- Pages
- 1682-1690
- ISSN
- 2374-7943 (ISSN-L)
- 2374-7951
- OpenAlex
- W2974217727
- Cited by
- 301
- References
- 9
- FWCI
- 9.38
- Type
- journal article
- Language
- en
- Open access
- diamond
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- Pfaff, P., Samarasinghe, K. T. G., Crews, C. M., & Carreira, E. M. (2019). Reversible Spatiotemporal Control of Induced Protein Degradation by Bistable PhotoPROTACs. ACS Central Science. https://doi.org/10.1021/acscentsci.9b00713
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