InACTIvAtion – Targeting Activin A through Fragment-based Drug Discovery and chemical-genetic approaches

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Increasing numbers of cancer patients with severe malignancies across Europe necessitate innovative therapeutic strategies to ensure the health and improved quality of life during and after treatment. Transforming growth factors (TGF-β) such as Activin A possess pro-tumourigenic effects, rendering this class a remarkable target for cancer treatment. Different strategies were reported, mainly utilizing biologics to interfere with Activin A signaling, showing limited specificity and affecting other TGF-β superfamily members. No interrogation with a drug-like molecule has been described for Activin A so far, which would provide several advantages. Hence, this project aims to validate this class of targets in a proof-of-concept study utilizing Fragment-based Drug Discovery (FBDD) to evolve small molecule inhibitors and chemical-genetic approaches to impair signalling of Activin A. The project will be carried out by a highly qualified researcher trained in chemical biology with expertise in structure-guided ligand design and innovative inhibition approaches for therapeutic advances in the context of cancer. Together with the supervisor, Prof. Hyvönen, who is recognised as a major contributor to the field of TGF-ß family growth factors, I will collaborate to address the druggability of Activin A. As an integral member of a multidisciplinary programme in FBDD at the University of Cambridge (UCAM), his group focusses on protein chemistry, biophysics, and X-ray crystallography. The engaging and international environment at UCAM will help me to develop a unique skillset, resulting in a mature profile to accelerate an independent research career across Europe. Besides, my chemical biology perspective, combined with Prof. Hyvönen’s expertise on Activin A proteins, will enable successful outcomes of the fellowship. Finally, setting the ground for future drug development of TGF-ß inhibitors in the context of cancer.