Centre for Targeted Protein Degradation: publications
With the Journal Club we aim to create a valuable resource for the wider scientific community to allow researchers in the field to keep up to date with TPD literature and share exciting research in chemical biology, structural biology, medicinal chemistry, and beyond.
Primary research papers
Targeted protein degradation via intramolecular bivalent glues
Oliver Hsia, Matthias Hinterndorfer, Angus D. Cowan, Kentaro Iso, Tasuku Ishida, Ramasubramanian Sundaramoorthy, Mark A. Nakasone, Hana Imrichova, Caroline Schätz, Andrea Rukavina, Koraljka Husnjak, Martin Wegner, Alejandro Correa-Sáez, Conner Craigon, Ryan Casement, Chiara Maniaci, Andrea Testa, Manuel Kaulich, Ivan Dikic, Georg E. Winter & Alessio Ciulli
Nature (2024) https://rdcu.be/dzfgN
Ternary Complex-Directed Dynamic Combinatorial Chemistry Enables Discovery of Potent VHL Homo-PROTACs.
Claudia Diehl, Alessandra Salerno, Alessio Ciulli*
ChemRxiv. Cambridge: Cambridge Open Engage; 2023; DOI: 10.26434/chemrxiv-2023-tz70z
Targeting cancer with small molecule pan-KRAS degraders
Johannes Popow, William Farnaby, Andreas Gollner, Christiane Kofink, Gerhard Fischer, Melanie Wurm, David Zollman, Andre Wijaya, Nikolai Mischerikow, Carina Hasenoehrl, Polina Prokofeva, Heribert Arnhof, Silvia Arce-Solano, Sammy Bell, Georg Boeck, Emelyne Diers, Aileen B Frost, Jake Goodwin-Tindall, Jale Karolyi-Oezguer, Shakil Khan, Theresa Klawatsch, Manfred Koegl, Roland Kousek, Barbara Kratochvil, Katrin Kropatsch, Arnel A Lauber, Ross McLennan, Sabine Olt, Daniel Peter, Oliver Petermann, Vanessa Roessler, Peggy Stolt-Bergner, Patrick Strack, Eva Strauss, Nicole Trainor, Vesna Vetma, Claire Whitworth, Siying Zhong, Jens Quant, Harald Weinstabl, Bernhard Küster, Peter Ettmayer*, Alessio Ciulli*
bioRxiv 2023.10.24.563163; doi: https://doi.org/10.1101/2023.10.24.563163
Structure-based design of a phosphotyrosine-masked covalent ligand targeting the E3 ligase SOCS2
Ramachandran, S., Makukhin, N., Haubrich, K., Nagala, M., Forrester, B., Lynch, D.M., Casement, R., Testa, A., Bruno, E., Gitto, R., Ciulli, A.*
Nat. Commun. 2023, 14, 6345
- PMID: 37816714 PMCID: PMC10564737
- See Figures on our Group website
- Preprint version 1 posted at ChemRxiv on 18 October 2022; DOI: 10.26434/chemrxiv-2022-bvj80
- Preprint version 2 updated at ChemRxiv on 16 August 2023; DOI: 10.26434/chemrxiv-2022-bvj80-v2
- X-ray crystallographic atomic coordinates and structure factors are available at the PDB under accession codes 7ZLP (compound 9 soaked to SBC2), 7ZLN (compound 11 soaked to SBC2), 7ZLO (compound 12 soaked to SBC2), 7ZLR (compound 13 soaked to SBC2), 7ZLS (compound 13 co-crystallized in complex with SBC2), 7ZLM (compound MN551 co-crystallized in complex with SBC2).
- Covered in University of Dundee News website
Targeted protein degradation via intramolecular bivalent glues
Oliver Hsia, Matthias Hinterndorfer, Angus D. Cowan, Kentaro Iso, Tasuku Ishida, Ramasubramanian Sundaramoorthy, Mark A. Nakasone, Hana Imrichova, Caroline Schätz, Andrea Rukavina, Koraljka Husnjak, Martin Wegner, Alejandro Correa-Sáez, Conner Craigon, Ryan Casement, Chiara Maniaci, Andrea Testa, Manuel Kaulich, Ivan Dikic, Georg E. Winter*, Alessio Ciulli*
bioRxiv 2023.02.14.528511; doi: https://doi.org/10.1101/2023.02.14.528511
- Preprint version 1 posted at BioRxiv on 14 February 2023; DOI: 10.1101/2023.02.14.528511v1
- Cryo-EM density maps are deposited in the EMDB with the accession code EMD-17172 and will be released upon publication. The atomic model is deposited under Protein Data Bank ID 8OV6.
Expanding the Structural Diversity at the Phenylene Core of Ligands for the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase: Development of Highly Potent Hypoxia-Inducible Factor-1alpha (HIF-1alpha) Stabilizers
Vu, L.P., Diehl, C.J., Casement, R., Bond, A.G., Steinebach, C., Strašek, N., Bricelj, A., Perdih, A., Schnakenburg, G., Sosič, I., Ciulli, A.*, Gütschow, M*
Med. Chem. 2023, 66 (18), 12776-12811
- PMID: 37708384 PMCID: PMC10544018
- See Figures on our Group website
- Pre-print first posted at ChemRxiv on 07 March 2023; DOI: 10.26434/chemrxiv-2023-5gbb6
- Newer version 2 available from August 1st, 2023 at 10.26434/chemrxiv-2023-5gbb6-v2
- The coordinates and structure factors of the associated co-crystal structure of the binary complexes between VHL and inhibitors 30, 33, and 37 are available in the PDB with accession codes 8CQK, 8CQL, and 8CQE, respectively
Proximity-Based Modalities for Biology and Medicine
Liu, X. Ciulli, A.*
ACS Cent. Sci. 2023, 9 (7), 1269–1284
- PMID: 37521793 PMCID: PMC10375889
- See Figures on our Group website
- Listed as 1st Most Read Article in the journal (1-month timeframe, Aug 2023)
Synthetic PROTACs based on a depsipeptide macrocycle selectively degrade cyclophilin A and inhibit HIV-1
15 March 2023, PREPRINT (Version 1) available at Research Square
Clara Gathmann, Lydia S Newton, Sophie Ridewood, Robert J Smith, Thomas W Hornsby, Ann-Kathrin Reuschl, Andre J Wijaya, Kate L Morling, Ying Ying Tan, Lucy G Thorne, Alessio Ciulli, Clare Jolly, Greg J Towers, David L Selwood
[https://doi.org/10.21203/rs.3.rs-2639894/v1]
Breaking free from the crystal lattice: Structural biology in solution to study protein degraders
Haubrich, K., Spiteri, V.A., Farnaby, W., Sobott, F., Ciulli, A.*
Curr. Opin. Struct. Biol., 2023, 79, 102534
- PMID: 36804675
- Ranked amongst Most Downloaded Articles in the journal (August 2023)
Crystallization of VHL-based PROTAC-induced ternary complexes
Wijaya, A.J., Farnaby, W., Ciulli, A.*
Methods Enzymol. 2023,681, 241-263
- PMID: 36764760
Functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Hanzl, A., Casement, R., Imrichova, H., Hughes, S.J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A.*, Winter, G.E.*
Nat. Chem. Biol. 2023, 19 (3), 323-333
- PMID: 36329119 PMCID: PMC7614256
- Pre-print posted at BioRxiv on 14 April 2022; DOI: https://doi.org/10.1101/2022.04.14.488316
- Covered in University of Dundee News website
- Covered in CeMM News website
- Highlighted in Nature Reviews Drug Discovery
- Featured in a Spotlight article by Nico Thoma and colleagues in Trends in Pharmacological Sciences
- Atomic coordinates and structure factors for the ternary complex crystal structure VHL:AT7:Brd4-BD2 are available at the PDB under accession code 7ZNT.
A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Kofink, C., Trainor, N., Mair, B., Wöhrle, S., Wurm, M., Mischerikow, N., Roy, M., Bader, G., Greb, P., Garavel, G., Diers, E., McLennan, R., Whitworth, C., Vetma, V., Rumpel, K., Scharnweber, M., Fuchs, J.E., Gerstberger, T., Cui, Y., Gremel, G., Chetta, P., Hopf, S., Budano, N., Rinnenthal, J., Gmaschitz, G., Mayer, M., Koegl, M., Ciulli, A., Weinstabl, H., Farnaby, W.
Nat. Commun. 2022, 13, 5969
- PMID: 36216795 PMCID: PMC9551036
- Pre-print posted at ChemRxiv on 1 February 2022; DOI: 10.26434/chemrxiv-2022-q63s3
- Covered in University of Dundee News website
- Featured in a Comment article by John Harling and Chris Tinworth in Nature Communication
- X-ray co-crystal structures data have been deposited to the PDB under accession codes 7Z78 (compound 4 in complex with SMARCA2-BD), 7Z6L (VCB: compound 5: SMARCA2-BD ternary complex), 7Z77 (VCB: compound 6: SMARCA2-BD ternary complex), and 7Z76 (VCB: compound 10: SMARCA2-BD ternary complex).
Discovery of benzo[d]imidazole-6-sulfonamides as Bromodomain and Extra-Terminal Domain (BET) Inhibitors with Selectivity for the First Bromodomain
Cipriano, A., Milite, C., Feoli, A., Viviano, M., Pepe, G., Campiglia, P., Sarno, G., Picaud, S., Imaide, S., Makukhin, N., Filippakopoulos, P., Ciulli, A., Castellano, S., Sbardella, G.
ChemMedChem 2022, 17 (20), e202200343
- PMID: 36040095 PMCID: PMC9826262
- See front cover on Chemistry Europe website
Discovery of XL01126: A Potent, Fast, Cooperative, Selective, Oral bioavailable and Blood Brain Barrier Penetrant PROTAC Degrader of Leucine Rich Repeat Kinase 2 (LRRK2)
Liu, X., Kalogeropulou, A., Domingos, S., Makukhin, N., Nirujogi, R., Singh, F., Shpiro, N., Saalfrank, A., Sammler, E., Ganley, I., Moreira, R., Alessi, D.*, Ciulli, A.*
J. Am. Chem. Soc., 2022, 144 (37), 16930–16952
Charting functional E3 ligase hotspots and resistance mechanisms to small-molecule degraders
Hanzl, A., Casement, R., Imrichova, H., Hughes, S.J., Barone, E., Testa, A., Bauer, S., Wright, J., Brand, M., Ciulli, A.*, Winter, G.E.*
BioRxiv 2022.04.14.488316; In Press at Nat. Chem. Biol.
A selective and orally bioavailable VHL-recruiting PROTAC achieves SMARCA2 degradation in vivo
Kofink, C., Trainor, N., Mair, B., Wöhrle, S., Wurm, M., Mischerikow, N., Roy, M., Bader, G., Greb, P., Garavel, G., Diers, E., McLennan, R., Whitworth, C., Vetma, V., Rumpel, K., Scharnweber, M., Fuchs, J.E., Gerstberger, T., Cui, Y., Gremel, G., Chetta, P., Hopf, S., Budano, N., Rinnenthal, J., Gmaschitz, G., Mayer, M., Koegl, M., Ciulli, A., Weinstabl, H.*, Farnaby, W.*
ChemRxiv. Cambridge: Cambridge Open Engage; February 1, 2022; In Press at Nat. Commun.
Amide-to-ester substitution as a strategy for optimizing PROTAC permeability and cellular activity
Klein, V.G., Bond, A.G., Craigon, C., Lokey, R.S.*, Ciulli, A.*
J. Med. Chem. 2021, 64 (24), 18082–18101
Trivalent PROTACs enhance protein degradation via combined avidity and cooperativity
Imaide, S., Riching, K.M., Makukhin, N., Vetma, V., Whitworth, C., Hughes, S.J., Trainor, N., Mahan, S.D., Murphy, N., Cowan, A.D., Chan, K.-H., Craigon, C., Testa, A., Maniaci, C., Urh, M., Daniels, D.L.*; Ciulli, A.*
Nat. Chem. Biol. 2021, 17 (11), 1157–1167
Development of BromoTag: A “Bump-and-Hole”–PROTAC System to Induce Potent, Rapid, and Selective Degradation of Tagged Target Proteins
Bond, A.G., Craigon, C., Chan, K.-H., Testa, A., Karapetsas, A., Fasimoye, R., Macartney, T., Blow, J.J., Alessi, D.R., Ciulli, A.*
Journal of Medicinal Chemistry Article ASAP, Oct 15, 2021.
J. Med. Chem. 2021, 64 (20), 15477–15502
Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay
Castro, G.V, Ciulli, A.*
RSC Med. Chem. 2021, 12, 1765-1770
Structure-Based Design of a Macrocyclic PROTAC
Testa, A., Hughes, S.J., Lucas, X., Wright, J.E., Ciulli, A.*
Angew. Chem. Int. Ed. 2020, 59, 1727-1734
BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design
Farnaby W, Koegl M, Roy MJ, Whitworth C, Diers E, Trainor N, Zollman D, Steurer S, Karolyi-Oezguer J, Riedmueller C, Gmaschitz T, Wachter J, Dank C, Galant M, Sharps B, Rumpel K, Traxler E, Gerstberger T, Schnitzer R, Petermann O, Greb P, Weinstabl H, Bader G, Zoephel A, Weiss-Puxbaum A, Ehrenhöfer-Wölfer K, Wöhrle S, Boehmelt G, Rinnenthal J, Arnhof H, Wiechens N, Wu MY, Owen-Hughes T, Ettmayer P, Pearson M, McConnell DB*, Ciulli A.*
Nat. Chem. Biol. 2019, 15, 672-680
Structural insights into substrate recognition by the SOCS2 E3 ubiquitin ligase
Kung, W.-W., Ramachandran, S., Makukhin, N., Bruno, E., Ciulli, A.*
Nat. Commun. 2019, 10, 2534
Rapid and reversible knockdown of endogenously tagged endosomal proteins via an optimized HaloPROTAC degrader
Tovell, H., Testa, A., Maniaci, C., Zhou, H., Prescott, A.R., Macartney, T., Ciulli, A.*, Alessi, D.R.*
ACS Chem. Biol. 2019, 14 (5), 882-892
Cereblon vs VHL: Hijacking E3 Ligases Against Each Other Using PROTACs
Girardini, M., Maniaci, C., Hughes, S.J., Testa, A., Ciulli, A.*
Bioorg. Med. Chem. 2019, 27 (12), 2466-2479
SPR-measured dissociation kinetics of PROTAC ternary complexes influence target degradation rate
Roy, M.J., Winkler, S., Hughes, S.J., Whitworth, C., Galant, M., Farnaby, W., Rumpel, K., Ciulli, A.*
ACS Chem. Biol. 2019, 14 (3), 361-368
Iterative design and optimization of initially inactive Proteolysis Targeting Chimeras (PROTACs) identify VZ185 as a potent, fast and selective von Hippel-Lindau (VHL)-based dual degrader probe of BRD9 and BRD7
Zoppi, V., Hughes, S.J., Maniaci, C., Testa, A., Gmaschitz, T., Wieshofer, C., Koegl, M., Riching, K., Daniels, D.L., Spallarossa, A., and Ciulli, A.*
J. Med. Chem. 2019, 62 (2), 699-726
3-Fluoro-4-hydroxyprolines: Synthesis, conformational analysis and stereoselective recognition by the VHL E3 ubiquitin ligase for targeted protein degradation
Testa, A., Lucas, X., Castro, G.V., Chan, K.-H., Wright, J.E., Runcie, A.C., Gadd, M.S., Harrison, W.T.A., Ko, E.-J., Fletcher, D., Ciulli, A.*
J. Am. Chem. Soc. 2018, 140 (29), 9299-9313
Homo-PROTACs: bivalent small-molecule dimerizers of the VHL E3 ubiquitin ligase to induce self-degradation
Maniaci, C., Hughes, S.J., Testa, A., Chen, W., Lamont, D.J., Rocha, S., Alessi, D.R., Romeo, R., Ciulli, A.*
Nat. Commun. 2017, 8, 830
Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex
Cardote, T.A.F., Gadd, M.S., Ciulli, A.*
Structure 2017, 25 (6), 901-911.e3
Structural basis of PROTAC cooperative recognition for selective protein degradation
Gadd, M.S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D.J., Zengerle, M., Ciulli, A.*
Nat. Chem. Biol. 2017, 13 (5), 514-521
Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition
Frost, J., Galdeano, C., Soares, P., Gadd, M.S., Epemolu, O., Grzes, K., Ellis, L., Shimamura, S., Bantscheff, M., Grandi, P., Read, K.D., Cantrell, D.A., Rocha, S., Ciulli, A.*
Nat. Commun. 2016, 7, 13312
Selective small molecules induced degradation of the BET bromodomain protein BRD4
Zengerle, M., Chan, K.-H., Ciulli, A.*
ACS Chem. Biol. 2015, 10 (8), 1770-1777
Structure-Guided Design and Optimization of Small Molecules Targeting the Protein-Protein Interaction between the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase and the Hypoxia Inducible Factor (HIF) Alpha Subunit with In Vitro Nanomolar Affinities
Galdeano, C., Gadd, M.S., Soares, P., Scaffidi, S., Van Molle, I., Birced, I., Hewitt, S., Dias, D.M., Ciulli A.*
J. Med. Chem. 2014, 57 (20), 8657-8663
Reviews
Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders.
Diehl, C.J., Ciulli, A.*
Chem. Soc. Rev. 2022, Advance Article. DOI: 10.1039/D2CS00387B
Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory
Cowan, A.D., Ciulli, A.*
Annu. Rev. Biochem., 2022, 91, 295-319
Targeting Epigenetic Modulators Using PROTAC Degraders: Current Status and Future Perspective
Webb, T., Craigon, C., Ciulli, A.*
Bioorg. Med. Chem. Lett. 2022, 63, 128653
Mechanistic and Structural Features of PROTAC Ternary Complexes, In: 'Targeted Protein Degradation'. Methods in Molecular Biology, vol 2365.
Casement R., Bond A., Craigon C., Ciulli A.*
Cacace A.M., Hickey C.M., Békés M. (eds) Humana, New York, NY, 2021. ISBN: 978-1-0716-1664-2
Methods Mol Biol. 2021, vol. 2365, pp. 79-113
A beginner’s guide to PROTACs and targeted protein degradation
Ciulli, A.*, Trainor, N.
Biochem (Lond) (2021)
Biochem (Lond) 2021, 43 (5), 74–79
Transforming targeted cancer therapy with PROTACs: A forward-looking perspective
Farnaby, W.*; Koegl, M.*; McConnell, D.B.; Ciulli, A.
Curr. Opin. Pharmacol. 2021, 57, 175-183
Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues
Ramachandran, S.; Ciulli, A.*
Curr. Opin. Struct. Biol. 2021, 67, 110-119
E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones
Ishida, T., Ciulli, A.*
SLAS Discov., 2021, 26 (4), 484-502
Bifunctional chemical probes inducing protein-protein interactions
Maniaci, C., Ciulli, A.*
Curr. Opin. Chem. Biol. 2019, 52, 145-156
Protein degradation for drug discovery. [Editorial]
Ciulli, A.*, Farnaby, W.*
Drug Discov. Today Technol. 2019 Apr 31: 1-3
Molecular recognition of ternary complexes: a new dimension in the structure-guided design of chemical degraders
Hughes, S.J., Ciulli, A.*
Essays in Biochemistry 2017, 61, 505-516
Journal Club
Targeted Protein Degradation and other literature highlights