Development of IWP-related compounds as selective wt/mutCK1d/e inhibitors, characterization in vitro and in vivo in animal models for their use in new anticancer concepts

本应用的目的是开发和优化新型酪蛋白激酶1 (CK1) d/e异构体/突变特异性抑制剂，并在体外（包括肿瘤培养）和动物模型中进行生物学表征。CK1亚型被认为是多种细胞过程的关键调节因子。CK1d/e亚型的活性和表达的改变与多种疾病的发展有关，包括神经退行性疾病和癌症。这一证据使得ck1亚型具有吸引力和有希望的治疗药物靶点。发现和分析新的治疗方法，包括活性小分子抑制剂，对癌症研究至关重要，可以整合到创新的癌症治疗概念中。潜在的新化合物可能在对化疗/放射治疗具有高耐药性和高突变率的侵袭性肿瘤实体（如三阴性乳腺癌）中证明是有益的，在这种情况下，常规治疗的有效性降低是造成高死亡率的原因。我们期望发现具有治疗潜力的新型小分子抑制剂，这可能有助于显著改善目前侵袭性肿瘤实体的治疗概念。

The aims of the present application are development and optimization of novel Casein Kinase 1 (CK1) d/e isoform/mutant-specific inhibitors, and their biological characterization in vitro, including tumor cultures, and in vivo using animal models. CK1 isoforms are known for being key regulators of diverse cellular processes. Alterations in the activity and expression of CK1d/e isoforms are linked to the development of several diseases, including neurodegenerative disorders and cancer. This evidence makes CK1isoforms attractive and promising therapeutic drug targets. The discovery and analysis of novel treatments, including active small molecule inhibitors, is of fundamental importance for cancer research and could be integrated into innovative cancer therapy concepts. Potential new compounds could prove beneficial in the case of aggressive tumor entities with high resistance to chemo/radiotherapy and high mutational rates, like triple negative breast cancer, where the reduced effectiveness of conventional treatments is responsible for high mortality rates. We expect to identify novel small molecule inhibitors with therapeutic potential which could contribute to a significant improvement in current treatment concepts for aggressive tumor entities.