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

失活 â 通过基于片段的药物发现和化学遗传学方法靶向激活素 A

• 批准号: 505091675
• 负责人: Dr. Lena Quambusch
• 金额: --
• 依托单位: Forschungsgebiet Chemische Biologie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/505091675?language=en
• 关键词: InACTIvAtion; Targeting; Activin; through; Fragment

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.

欧洲越来越多的严重恶性肿瘤患者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改善。转化生长因子（TGF-β）如激活素A具有促肿瘤发生作用，使得这类因子成为癌症治疗的显著靶标。报道了不同的策略，主要利用生物制剂干扰激活素A信号传导，显示出有限的特异性并影响其他TGF-β超家族成员。到目前为止，还没有描述用药物样分子对激活素A进行询问，这将提供几个优点。因此，该项目旨在利用基于片段的药物发现（FBDD）的概念验证研究中验证这类靶标，以发展小分子抑制剂和化学遗传方法来损害激活素A的信号传导。该项目将由一名经过化学生物学培训的高素质研究人员进行，该研究人员在结构指导配体设计和创新抑制方法方面具有专业知识，可用于癌症的治疗进展。我将与导师Hyvönen教授（他被公认为TGF-β家族生长因子领域的主要贡献者）合作，解决激活素A的可药用性问题。作为剑桥大学（UCAM）FBDD多学科项目的一员，他的团队专注于蛋白质化学，生物物理学和X射线晶体学。在UCAM的参与和国际环境将帮助我发展一个独特的技能，从而在一个成熟的配置文件，以加快整个欧洲的独立研究生涯。此外，我的化学生物学观点，结合Hyvönen教授在激活素A蛋白方面的专业知识，将使奖学金取得成功。最后，为未来在癌症背景下开发TGF-β抑制剂的药物奠定基础。