Development of Quinoxaline Based IKKbeta Inhibitors for Kras Driven Cancers

点击翻译按钮获取中文摘要

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.