Targeting oncofetal IGF2BP proteins by small molecule drugs in cancer

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Oncofetal IGF2 mRNA-binding proteins (IGF2BPs) are key modulators of human stem and cancer cell fate. In cancer cells their major role is the m6A-dependent regulation of mRNA turnover to enhance the expression of oncogenes like MYC. Recent studies suggest that the four KH domains of IGF2BPs facilitating RNA association and that RNA binding is druggable by small molecules. However, the molecular basis of RNA binding and inhibition remains to be explored for rational drug developments. The main objective of the proposed studies is to explore and improve lead compounds, including reversible, covalent small molecule inhibitors as well as proteolysis targeting chimeras (PROTACs), which are suitable to impair or degrade IGF2BP1 in cancer. In exploratory approaches, we furthermore aim to transfer knowledge gained by these studies to identify, evaluate and improve cysteine-directed compounds engaging with IGF2BP3 and additional oncofetal RNA binding proteins (RBPs). To this end, we have gathered a research team providing complementary expertise required for Structure-Activity-Relation (SAR) guided pre-clinical development of small molecule inhibitors and PROTACs of RBPs. In the proposed research consortium, we accordingly bundle expertise in the chemical development of small molecule inhibitors (Sippl), the investigation of RBP-SARs by protein NMR spectroscopy (Balbach), and characterizing impaired RBP function in cancer models (Hüttelmaier) for the following research pipeline: A variety of IGF2BP inhibitors and PROTACs will be synthesised based on the scaffold of already found hit compounds J5 and BTYNB and tested in primary in vitro and in cellulo assays. Potent lead compounds will be further optimized based on structural and biophysical RNA binding elucidations at molecular resolution before a pre-clinical evaluation of the cellular efficacy, on- and off-targets, and synergies with other inhibitory treatments in various tumor models.