Centre for Targeted Protein Degradation: publications

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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 here
  • 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 UoD 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

Proximity-Based Modalities for Biology and Medicine

Liu, X. Ciulli, A.*
ACS Cent. Sci. 2023, 9 (7), 1269–1284

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

Crystallization of VHL-based PROTAC-induced ternary complexes

Wijaya, A.J., Farnaby, W., Ciulli, A.*
Methods Enzymol. 2023, 681, 241263

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

 

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 UoD 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

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.2022144 (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. 202164 (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. 202117 (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. 202164 (20), 15477–15502

Estimating the cooperativity of PROTAC-induced ternary complexes using 19F NMR displacement assay

Castro, G.V, Ciulli, A.*
RSC Med. Chem. 202112, 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. 201915, 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. 201910, 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. 201914 (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. 201927 (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. 201914 (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. 201962 (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. 2018140 (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. 20178, 830

Crystal Structure of the Cul2-Rbx1-EloBC-VHL Ubiquitin Ligase Complex

Cardote, T.A.F., Gadd, M.S., Ciulli, A.*
Structure 201725 (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. 201713 (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. 20167, 13312

Selective small molecules induced degradation of the BET bromodomain protein BRD4

Zengerle, M., Chan, K.-H., Ciulli, A.*
ACS Chem. Biol. 201510 (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. 201457 (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.202291, 295-319

Targeting Epigenetic Modulators Using PROTAC Degraders: Current Status and Future Perspective

Webb, T., Craigon, C., Ciulli, A.*
Bioorg. Med. Chem. Lett. 202263, 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) 202143 (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. 202157, 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. 202167, 110-119

E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones

Ishida, T., Ciulli, A.*
SLAS Discov.202126 (4), 484-502

Bifunctional chemical probes inducing protein-protein interactions

Maniaci, C., Ciulli, A.*
Curr. Opin. Chem. Biol. 201952, 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 201761, 505-516

Journal Club

Ciulli Group Journal Club

Targeted Protein Degradation and other literature highlights

Ciulli Group Journal Club

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.​