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

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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.