University of Dundee

Professor Alessio Ciulli FRSC

Chemical and Structural Biology of Targeted Protein Degradation
Position: 
Professor of Chemical and Structural Biology and Director of the Centre for Targeted Protein Degradation
Address: 
School of Life Sciences, University of Dundee, Dundee
Full Telephone: 
+44 (0) 1382 386230, int ext 86230
Email: 

Research

The Ciulli Laboratory develops novel small molecules targeting protein degradation and protein interactions. We do research on fundamental chemical biology and translate it via collaboration partnership with the biopharma industry and by creation of spin-out companies.

Pioneering discoveries from the Laboratory and others over the past decade have contributed to the advent of a new modality of chemical intervention to study biology and drugs to cure disease. Instead of blocking a target protein as conventionally done with inhibitors, we are designing “tailored” bifunctional molecules that bring a target protein to an E3 ubiquitin ligase for targeted protein degradation. We have illuminated important understanding of how this new class of molecules work that is beginning to define the rules and principles of how to design and study them.

Our research in this area takes a multidisciplinary approach including organic and medicinal chemistry and computational tools to design and achieve desired molecules; structural biology and biophysics to study binary and ternary complexes in solution and reveal their structural and dynamic interactions; and chemical biology, biochemistry, proteomics and cell biology to study the cellular impact of our small molecules into relevant cellular systems and disease models, in collaboration with pathways biologists and medics.

Current research efforts are directed towards:

1. Design and development of PROTACs as chemical tools for probing the biological function and therapeutic potential of compelling targets in cancer and other diseases

2. Structure-guided fragment-based design of novel E3 ligase binding ligands

3. Biochemical, biophysical and structural studies of novel E3 ubiquitin ligases

4. Novel approaches to small-molecule inducible degron technologies

Teaching

BS42011:  A 4th year module entitled "Advanced Chemical Biology"

Publications

1. Bond A, Testa A, Ciulli A. 2020. Stereoselective synthesis of allele-specific BET inhibitors. Organic and Biomolecular Chemistry. 18(38):7533-7539.  (Read Online)

2. Cipriano A, Sbardella G, Ciulli A. 2020. Targeting epigenetic reader domains by chemical biology. Current Opinion in Chemical Biology.  (Read Online)

3. Ishida T, Ciulli A. 2020. E3 Ligase Ligands for PROTACs: How They Were Found and How to Discover New Ones . SLAS Discovery. (Read Online)

4. Klein VG, Townsend CE, Testa A, Zengerle M, Maniaci C, Hughes SJ, Chan K-H, Ciulli A, Lokey RS. 2020. Understanding and Improving the Membrane Permeability of VH032-Based PROTACs. ACS Medicinal Chemistry Letters. 11(9):1732-1738.  (Read Online)

5. Makukhin N, Ciulli A. 2020. Recent advances in synthetic and medicinal chemistry of phosphotyrosine and phosphonate-based phosphotyrosine analogues. RSC Medicinal Chemistry. (Read Online)

6. Ramachandran S, Ciulli A. 2021. Building ubiquitination machineries: E3 ligase multi-subunit assembly and substrate targeting by PROTACs and molecular glues. Current Opinion in Structural Biology. 67:110-119.  (Read Online)

7. Simpson LM, Macartney TJ, Nardin A, Fulcher LJ, Röth S, Testa A, Maniaci C, Ciulli A, Ganley IG, Sapkota GP. 2020. Inducible Degradation of Target Proteins through a Tractable Affinity-Directed Protein Missile System. Cell Chemical Biology. 27(9):1164-1180.e5. (Read Online)

8. Testa, A., Hughes, S.J.,  Lucas, X., Wright, J.E., Ciulli, A. 2020 Structure-Based Design of a Macrocyclic PROTAC. Angew. Chem. Int. Ed., 59, 1727-1734. (Read Online)

9. Whitworth, C., Ciulli, A. 2020 Protein degraders extend their reach. Nature, 584, 193-194. (Read Online)

10. Zollman D, Ciulli A. 2020. Structural and Biophysical Principles of Degrader Ternary Complexes. Weinmann H, Crews C, editors. In Protein Degradation with New Chemical Modalities: Successful Strategies in Drug Discovery and Chemical Biology. 74 ed. Royal Society of Chemistry. pp. 14-54. (RSC Drug Discovery Series; 74). (Read Online)

11. A. C. Runcie, M. Zengerle, K.-H. Chan, A. Testa, L. van Beurden, M. G. J. Baud, O. Epemolu, L. C. J. Ellis, K. D. Read, V. Coulthard, A. Brien, A. Ciulli* Optimization of a “Bump-and-Hole” Approach to Allele-Selective BET Bromodomain Inhibition. Chem. Sci., 2018, 9, 2452–2468. (Read Online)

12. Maniaci, C., Hughes, S.J., Testa, A., Rocha, S., Alessi, D.R., Romeo, R., Ciulli, A.* Homo­PROTACs: bivalent small­molecule dimerizers of the VHL E3 ubiquitin ligase to induce self­degradation. Nat. Commun. 2017 8, 830. (Read Online)

13. Cardote, T.A.F., Gadd, M.S., Ciulli, A.* Crystal structure of the Cul2-Rbx1-EloBC-VHL ubiquitin ligase complex. Structure 2017, 25, 901–911. (Read Online)

14. Gadd, M.S., Testa, A., Lucas, X., Chan, K.-H., Chen, W., Lamont, D.J., Zengerle, M., Ciulli, A.* Structural basis of PROTAC cooperative recognition for selective protein degradation. Nat. Chem. Biol. 2017, 13(5), 514–521. (Read Online)

15. Frost, J., Galdeano, C., Soares, P., Gadd, M.S., Grzes, K.M., Ellis, L., Epemolu, O., Shimamura, S., Bantscheff, M., Grandi, P., Read, K.D., Cantrell, D.A., Rocha, S., Ciulli, A.* Potent and selective chemical probe of hypoxic signalling downstream of HIF-α hydroxylation via VHL inhibition. Nat. Commun. 2016, 7, 13312. (Read Online)

16. Zengerle, M., Chan, K.-H., Ciulli, A.* Selective small molecules induced degradation of the BET bromodomain protein BRD4. ACS Chem. Biol. 2015, 10(8), 1770–1777 (Read Online)

17. Baud, M.G.J., Lin-Shiao, E., Cardote, T., Tallant, C., Pschibul, A., Chan, K.-H., Zengerle, M., Garcia, J.R., Kwan, T.T.-L., Ferguson, F.M., Ciulli, A.* A bump-and-hole approach to engineer controlled selectivity of BET bromodomain chemical probes. Science, 2014, 346, 638–641. (Read Online)

18. Galdeano, C., Gadd, M., Soares, P., Scaffidi, S., Van Molle, I., Birced, I., Hewitt, S., Dias, D.M., Ciulli, A.* Structure-Guided Design and Optimization of Small Molecules Targeting the VHL E3 Ubiquitin Ligase and Disrupting its Interaction with HIF-1a with Nanomolar Affinities. J. Med. Chem., 2014, 57(20), 8657–8663. (Read Online)

19. Silvestre, H.L., Blundell, T.L., Abell, C., Ciulli, A.*  Integrated biophysical approach to fragment screening and validation for fragment-based lead discovery. Proc. Natl. Acad. Sci. Usa, 2013, 110, 12984–12989 (Read Online)

20. Van Molle, I., Thomann, A., Buckley, D.L., So, E.C., Lang, S., Crews, C.M., Ciulli, A.* Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:Hypoxia Inducible Factor 1a protein-protein interface. Chem. Biol. 2012, 19, 1300–1312. (Read Online)