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

通过FGF/FGFR信号传递网络的过度促有丝分裂信号传导诱导与转移表型和不良临床结局相关的破坏性致癌作用。FGF 2是FGF家族的原型成员，具有作为肿瘤细胞存活因子的既定作用。在病理生理条件下限制FGF 2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，因为这些药物具有冗余的FGF信号级联和强烈的细胞毒性副作用。为了克服这些局限性，该知识转移项目旨在开发一类新的抑制剂，以不同的水平阻止FGF 2的病理生理功能，肿瘤细胞及其细胞微环境分泌FGF 2。由于最近的发现揭示了FGF 2的非常规分泌途径的分子机制，确定了药物开发的两个靶点。一方面，我们的目标是蛋白质-蛋白质相互作用抑制剂，其阻断由Tec激酶介导的FGF 2的酪氨酸磷酸化，Tec激酶是FGF 2分泌的调节组分。另一方面，我们将开发一种新型的自杀抑制剂，旨在靶向FGF 2分子表面上的一个关键半胱氨酸残基，该残基是FGF 2非常规分泌的关键中间体，是寡聚化和膜孔形成所需的。所描述的抑制剂作为先导化合物具有很大的潜力，用于开发新型抗癌药物，防止FGF 2作为肿瘤细胞存活因子发挥作用。

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.