Centre for Targeted Protein Degradation: publications

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Primary research papers

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



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.​