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

欧洲各地患有严重恶性肿瘤的癌症患者数量不断增加，这就需要创新的治疗策略，以确保治疗期间和治疗后的健康和生活质量的提高。转化生长因子(转化生长因子-β)，如激活素A，具有促肿瘤作用，使这一类别成为癌症治疗的显著靶点。报道了不同的策略，主要是利用生物制剂干扰激活素A信号转导，显示出有限的特异性，并影响其他转化生长因子-β超家族成员。到目前为止，还没有关于激活素A的类似药物分子的询问的描述，这将提供几个优点。因此，该项目的目标是在一项概念验证研究中验证这类靶点，该研究利用基于片段的药物发现(FBDD)来进化小分子抑制剂和化学遗传方法以削弱激活素A的信号传递。该项目将由一名受过化学生物学培训的高素质研究人员执行，该研究人员具有结构导向配体设计和创新抑制方法方面的专业知识，可用于癌症治疗方面的进展。与被公认为是转化生长因子家族生长因子领域主要贡献者的主管Hyvönen教授一起，我将合作解决Activin A的可药性问题。作为剑桥大学(UCAM)FBDD多学科项目的重要成员，他的团队专注于蛋白质化学、生物物理学和X射线结晶学。UCAM吸引人的国际化环境将帮助我发展一套独特的技能，使我拥有成熟的个人资料，加快整个欧洲的独立研究事业。此外，我的化学生物学观点，结合Hyvönen教授在激活素A蛋白质方面的专业知识，将使该奖学金取得成功。最后，为未来在癌症背景下开发转化生长因子-贝类抑制剂奠定了基础。

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.