Development of small molecule inhibitors blocking unconventional secretion of Fibroblast Growth Factor 2, a potent tumour cell survival factor - Knowledge Transfer Project

开发小分子抑制剂，阻断成纤维细胞生长因子 2 的非常规分泌，成纤维细胞生长因子 2 是一种有效的肿瘤细胞存活因子 - 知识转移项目

• 批准号: 389866291
• 负责人: Professor Dr. Walter Nickel
• 金额: --
• 依托单位: Europäisches Laboratorium für Molekularbiologie (EMBL)
• 依托单位国家: 德国
• 项目类别: Research Grants (Transfer Project)
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/389866291?language=en
• 关键词: Development; small; molecule; inhibitors; blocking

Excessive mitogenic signalling through FGF/FGFR signal transmission networks induces devastating carcinogenic effects associated with metastatic phenotypes and poor clinical outcomes. FGF2 is the prototype member of the FGF family with an established role as a tumor cell survival factor. Classical approaches to limit FGF2 function under pathophysiological conditions were based upon inhibitors that target FGF receptor tyrosine kinases. These strategies proved challenging due to redundant FGF signalling cascades and strong cytotoxic side effects of such drugs. To overcome these limitations, this knowledge transfer project aims at developing a new class of inhibitors that prevent the pathophysiological functions of FGF2 at a different level, the secretion of FGF2 by tumour cells and their cellular microenvironment. Due to recent discoveries revealing the molecular mechanism of the unconventional secretory pathway of FGF2, two targets for drug development were identified. On the one hand, we aim at protein-protein interaction inhibitors that block tyrosine phosphorylation of FGF2 mediated by Tec kinase, a regulatory component of FGF2 secretion. On the other hand, we will develop a new type of suicide inhibitor designed to target a critical cysteine residue on the molecular surface of FGF2 required for oligomerization and membrane pore formation, the key intermediate in unconventional secretion of FGF2. The inhibitors described have great potential as lead compounds for the development of novel anti-cancer drugs preventing FGF2 from functioning as a tumor cell survival factor.

通过FGF/FGFR信号传递网络的过量有丝分裂信号可诱导与转移表型和不良临床结果相关的破坏性致癌作用。FGF2是FGF家族的原型成员，已确定其作为肿瘤细胞存活因子的作用。在病理生理条件下限制FGF2功能的经典方法是基于靶向FGF受体酪氨酸激酶的抑制剂。这些策略被证明是具有挑战性的，因为这些药物存在冗余的FGF信号级联反应和强烈的细胞毒性副作用。为了克服这些限制，该知识转移项目旨在开发一类新的抑制剂，以在不同水平上阻止FGF2的病理生理功能，肿瘤细胞及其细胞微环境分泌FGF2。由于最近的发现揭示了FGF2非常规分泌途径的分子机制，确定了两个药物开发靶点。一方面，我们的目标是蛋白-蛋白相互作用抑制剂，它可以阻断由Tec激酶介导的FGF2的酪氨酸磷酸化，Tec激酶是FGF2分泌的调节成分。另一方面，我们将开发一种新型自杀抑制剂，旨在针对FGF2分子表面上寡聚和膜孔形成所需的关键半胱氨酸残基，这是FGF2非常规分泌的关键中间体。所描述的抑制剂具有很大的潜力，可以作为开发新型抗癌药物的先导化合物，阻止FGF2作为肿瘤细胞存活因子的功能。