Targeting oncofetal IGF2BP proteins by small molecule drugs in cancer

癌胎儿IGF2mRNA结合蛋白(IGF2BP)是调节人类干细胞和癌细胞命运的关键因子。在癌细胞中，它们的主要作用是依赖于m6A调节mRNA周转，以增强MYC等癌基因的表达。最近的研究表明，IGF2BP的四个KH结构域促进了RNA的结合，并且RNA结合是可被小分子抑制的。然而，RNA结合和抑制的分子基础仍有待于合理的药物开发。这项研究的主要目的是探索和改进先导化合物，包括可逆的共价小分子抑制剂以及针对嵌合体的蛋白水解靶向(PROTAC)，这些化合物适合于在癌症中削弱或降解IGF2BP1。在探索性方法中，我们的进一步目标是转移从这些研究中获得的知识，以识别、评估和改进与IGF2BP3和其他癌胎儿RNA结合蛋白(RBPs)相结合的半胱氨酸导向化合物。为此，我们聚集了一个研究团队，为结构-活性-关系(SAR)指导的小分子抑制剂和限制性商业惯例的PROTAC的临床前开发提供所需的补充专业知识。因此，在拟议的研究财团中，我们捆绑了小分子抑制剂(SIPPL)的化学开发、通过蛋白质核磁共振波谱(Balbach)调查RBP-SARS以及在癌症模型(Hüttelmaier)中表征RBP功能受损的专业知识，用于以下研究管道：将基于已发现的Hit化合物J5和BTYNB的支架合成各种IGF2BP抑制剂和PROTAC，并进行体外和细胞分析的初步测试。有效的先导化合物将在分子分辨率的结构和生物物理RNA结合阐明的基础上进一步优化，然后在各种肿瘤模型中对细胞效率、靶点内外以及与其他抑制治疗的协同作用进行临床前评估。

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.