Targeting oncofetal IGF2BP proteins by small molecule drugs in cancer

小分子药物靶向癌症胎儿 IGF2BP 蛋白治疗癌症

• 批准号: 510840397
• 负责人: Professor Dr. Jochen Balbach
• 金额: --
• 依托单位: Institut für Molekulare Medizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/510840397?language=en
• 关键词: Targeting; oncofetal; IGF2BP; proteins; small

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.

肿瘤胎儿IGF2 mrna结合蛋白（igf2bp）是人类干细胞和癌细胞命运的关键调节剂。在癌细胞中，它们的主要作用是依赖m6a调控mRNA转换，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RNA结合，并且RNA结合可被小分子药物治疗。然而，RNA结合和抑制的分子基础仍有待探索，以便合理开发药物。这些研究的主要目的是探索和改进先导化合物，包括可逆性、共价小分子抑制剂以及蛋白水解靶向嵌合体（PROTACs），它们适合损害或降解癌症中的IGF2BP1。在探索性方法中，我们进一步致力于将这些研究获得的知识用于识别、评估和改进与IGF2BP3和其他癌胎RNA结合蛋白（rbp）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rbp的小分子抑制剂和PROTACs的临床前开发提供结构-活性-关系（SAR）指导所需的补充专业知识。在拟议的研究联盟中，我们将结合小分子抑制剂的化学开发（Sippl）， RBP- sars的蛋白质NMR研究（Balbach），以及癌症模型中RBP功能受损的特征（h<s:1> ttelmaier）方面的专业知识，用于以下研究管道：各种IGF2BP抑制剂和PROTACs将基于已经发现的hit化合物J5和BTYNB的支架合成，并在体外和细胞分析中进行初步测试。在对各种肿瘤模型的细胞疗效、靶标和非靶标以及与其他抑制治疗的协同作用进行临床前评估之前，将基于分子分辨率的结构和生物物理RNA结合阐明进一步优化有效的先导化合物。