Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers

项目摘要 IKK β的激活与炎症有关，并且在小鼠模型中加速 在癌基因存在下的肿瘤发生或肿瘤抑制基因的缺失。四种IKK β抑制剂 进入临床试验，但由于安全性不佳、缺乏疗效或 组合重新定位。MAP 3 K1是磷酸化IKKb的上游激酶， 与胰腺癌患者的5年生存率较差相关，使其成为一个有吸引力的治疗靶点。 我们最近报道了一种MAP 3 K1抑制剂（IKAM-1）的发现，它可以降低p-IKKb水平，减少肿瘤的发生， Krasmutation驱动的胰腺癌的生长和转移。结构导向修饰验证IKAM-1 结合模式，并确定2作为改进的抑制剂。12个蛋白水解靶向嵌合体（PROTAC） 目前在临床试验中，PROTAC正迅速成为药物发现的主流方法。合成 使用2作为头基，对一组集中的PROTAC进行评价，发现50-008， 在269种癌细胞系中显示出广泛的抗癌活性，IC 50 < 100 nM。在本申请中，我们提出， （a）进行RNA-seq和蛋白质组范围的筛选以阐明作用机制，（B）优化 通过优化接头构象有效性和（c）在类器官中评价50-008或改进的类似物 和肿瘤模型。这些研究将确定具有适用于IND的明确MOA的主要候选药物，从而产生毒性 问题研究

Project Summary Activation of IKKbeta has been implicated in inflammation and in mouse models accelerates tumorigenesis in the presence of an oncogene or the loss of tumor suppressor gene. Four IKKbeta inhibitors entered clinical trials however none were FDA approved due to unfavorable safety profile, lack of efficacy or portfolio repositioning. MAP3K1 is an upstream kinase that phosphorylates IKKb and higher MAP3K1 levels is associated with poorer 5-year survival in pancreatic cancer patients, making it an attractive therapeutic target. We recently reported the discovery of a MAP3K1 inhibitor (IKAM-1) that reduced p-IKKb levels, reduced tumor growth and metastasis in Krasmutation driven pancreatic cancer. Structure-guided modification validated IKAM-1 binding mode and identified 2 as an improved inhibitor. With 12 proteolysis targeting chimeras (PROTACs) currently in clinical trials PROTACs are rapidly emerging as a mainstream approach in drug discovery. Synthesis and evaluation of a focused set of PROTACs using 2 as the head group led to the identification of 50-008 that exhibited broad anticancer activities with IC50 < 100 nM in 269 cancer cell lines. In this application we propose, to (a) conduct RNA-seq and proteome-wide screens to elucidate the mechanism of action, (b) optimize for efficacy through optimization of linker conformation and (c) evaluate 50-008 or an improved analog in organoids and tumor models. These studies will identify a lead candidate with defined MOA suitable for IND enabling toxicity studies.