Stabilising protein-protein interactions
Protein-protein interactions (PPIs) represent an exciting yet challenging class of drug target to have emerged over recent years. With over 300,000 PPIs estimated in humans, and many shown to be implicated in disease, the discovery of small-molecule modulators of these interactions is of great interest. Whilst a vast number of de novo PPI inhibitors such as the Nutlins have been successfully developed, only a handful of complex natural product-derived PPI stabilisers such as paclitaxel (Taxol) have been exploited in the clinic (although to great effect). The number of reported synthetic stabilisers is growing, but the mode-of-action for the vast majority of these examples has been defined in a post hoc fashion. The development of rational strategies for the discovery of de novo PPI stabilisers therefore represents a significant and as yet unmet scientific challenge.
My research is focused on developing chemical biology approaches that will allow us to meet this challenge. Specifically, my interests lie in molecules that act at a given PPI interface and thus (might) act like a ‘molecular glue’. Underpinned by synthetic organic chemistry, two core research avenues focus on enhancing our molecular understanding of PPI stabilisation and establishing improved ligand-discovery techniques.
Better understanding of PPI stabilisation at the atomic level is essential in order to design more synthetically tractable, selective and potent small molecules. To achieve this a combination of in silico evaluation, synthesis, biophysical and structural evaluation is being used to enhance our understanding of natural product PPI stabilisers. As a case in point, the mechanism for fusicoccin A stabilisation of 14-3-3 protein interaction with p53 is not well understood.
The development of assay technologies geared toward the identification of small molecule PPI stabilisers is essential for driving drug discovery. An approach that is currently under investigation seeks to harness the complexity of protein-drug-protein ternary complexes through protein-templated synthesis.
An extension of this work will be to better understand and evaluate small molecule PPI stabilisation in a cellular context. Thus, the development of disease-relevant cell-based assays is of great interest looking into the near future.
- R. M. J. M. de Vries, F. A. Meijer, R. G. Doveston, I. A. Leijten-van de Gevel, L. Brunsveld Cooperativity Between the Orthosteric and Allosteric Binding Sites of RORγt, Proc. Nat. Acad. Sci. 2021. DOI: 10.1073/pnas.2021287118
- Falcicchio M, Ward JA, Macip Sand Doveston RG.R egulation of p53 by the 14-3-3 protein interaction network: new opportunities for drug discovery in cancer, Cell Death Discovery 6, 126.
- Fragment-based Differential Targeting of PPI Stabilizer Interfaces, J. Med. Chem. (2020), 63, 13, 6694–6707 https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.9b01942
- Elucidation of an Allosteric Mode-of-Action for a Thienopyrazole RORgt Inverse Agonist, R. M. J. M. de Vries, F. A. Meijer, R. G. Doveston, L. Brunsveld – ChemMedChem (2020), 15(7): 561–565.
- Ligand-based Design of Allosteric RORγt Inverse Agonists, R.G. Doveston, F. A. Meijer, R. M. J. M. de Vries, G. Vos, A. Vos, M. Scheepstra, S. Leysen, C. Ottmann, L.-G. Milroy and L. Brunsveld – J. Med. Chem. (2020), 241-259.
- Kuusk A, et al (2020) Adoption of a Turn Conformation Drives the Binding Affinity of p53 C-Terminal Domain Peptides to 14-3-3σ.' ACS Chem Biol. 15(1):262-271. doi: 10.1021/acschembio.9b00893
Marta Falcicchio, Alisha Mohindra, Beth Thurairajah and Jake Ward.
Bench to Business
See Richard's Bench to Business film.