InACTIvAtion – Targeting Activin A through Fragment-based Drug Discovery and chemical-genetic approaches
Biochemistry
Biological and Biomimetic Chemistry
Pharmacy
Final Report Abstract
Cancer, which affects one in three Europeans, remains a major healthcare challenge. With increasing numbers of patients diagnosed with cancer due to demographic changes and environmental factors, there is a critical need for new and more effective therapeutic strategies. One of the key biological processes that drive cancer progression is the signalling of transforming growth factors (TGF-β), which can promote tumour growth, spread, and resistance to cell death. Among these, Activin A, a member of the TGF-β family, plays a crucial role in these cancer-related processes. Beyond cancer, Activin A also regulates muscle mass and is emerging as a therapeutic target in obesity treatment, especially with GLP-1 antagonists, where its inhibition could prevent muscle loss during therapy. Current treatment strategies targeting Activin A mainly rely on neutralising antibodies or receptor ligand traps, but these have limitations, such as bad pharmacokinetics, reduced specificity (in case of ligand traps) and effects on other related molecules in the TGF-β family. There has been little research into using small drug-like molecules to target Activin A directly. This project aims to fill that gap by developing small molecules that can selectively block Activin A's signalling, which could provide a more focused and effective treatment. Fragment-based drug discovery (FBDD) is an innovative technique that helps identify small molecules capable of binding to specific protein targets. This method uses X-ray crystallography to provide detailed structural information about the binding sites of these molecules. For Activin A, we worked to optimize its solubility, which allowed us to develop high-quality crystals and perform an extensive fragment screening at the XChem facility at Diamond Light Source. This screening generated over 1400 datasets, leading to the successful identification of around 100 distinct fragment molecules that bind to Activin A. Among the identified fragments, 60 specifically targeted the type I receptor binding site, the key interface where Activin A interacts with its signal transducing receptors. To validate these findings, we used a series of assays, including a BLI competition assay and an in-solution NMR binding test. These confirmed that the fragments not only bind to Activin A but also interfere with its natural binding to the receptor, offering a new potential strategy for activin inhibition. The results of this project set the stage for further development of small-molecule inhibitors that could block the harmful effects of Activin A in disease. By using FBDD and advanced structural biology techniques, we have made significant progress toward developing more targeted therapies for various indications. Our findings demonstrate the feasibility of such approaches and opens new avenues for drug development targeting TGF-β-like signalling pathways using small molecules.
Publications
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GitHub repository: 3D printing SOP “From PyMOL to Printable 3D Model”, Python code for plots, Scripts for uniform PyMOL sessions and figures.
Quambusch, Lena
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Profiling human hypothalamic neurons reveals a candidate combination drug therapy for weight loss. openRxiv.
Chen, Hsiao-Jou Cortina; Yang, Andrian; Mazzaferro, Simone; Mali, Iman; Cahn, Olivier; Kentistou, Katherine; Rowley, Christine; Stewart, Natasha; Seah, Jun Wen Eugene; Pisupati, Venkat; Kirwan, Peter; Aggarwal, Sanya; Toyohara, Takafumi; Florido, Mary H.C.; Cowan, Chad A.; Quambusch, Lena; Hyvönen, Marko; Livesey, Matthew R.; Perry, John R.B. ... & Merkle, Florian T.
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Conference Poster and Flash talk, “Chemical Biology Approach to Impair Signalling of Activin A”, EMBO Workshop: Chemical biology 2024, 09.-12.09.2024, EMBL, Heidelberg, Germany.
Quambusch, Lena
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Conference Poster, “Overcoming Promiscuity: Small Molecule Screening Strategy to Target Activin A”, Frontiers in Medicinal Chemistry 2024, 17.-20.03.2024, Munich, Germany.
Quambusch, Lena
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Seminar, “Innovative drugs and how to find them”, Fitzwilliam College Postdoc Society, 15.05.2024, Cambridge, UK.
Quambusch, Lena
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Short talk, “Targeting activin A through fragment-based drug discovery”, Biochemistry Postdoc Symposium, 19.09.2024, Cambridge, UK.
Quambusch, Lena
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Structure of mature Activin A from DMSO solvent optimisation of XChem fragment screen. Worldwide Protein Data Bank. Worldwide Protein Data Bank.
Quambusch, L. & Hyvonen, M.
