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

本申请的目的是开发和优化新的酪蛋白激酶1（CK 1）d/e同种型/突变体特异性抑制剂，以及它们在体外（包括肿瘤培养物）和体内（使用动物模型）的生物学表征。已知CK 1亚型是多种细胞过程的关键调节因子。CK 1d/e亚型的活性和表达的改变与几种疾病的发展有关，包括神经退行性疾病和癌症。这一证据使CK 1亚型成为有吸引力和有前途的治疗药物靶点。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。潜在的新化合物可以证明在对化疗/放疗具有高抗性和高突变率的侵袭性肿瘤实体的情况下是有益的，如三阴性乳腺癌，其中常规治疗的有效性降低是导致高死亡率的原因。我们期望鉴定出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.