Abstract 3645: A non-ATP competitive IKKβ inhibitor for cancer therapy

Abstract

Abstract Kinases are promising targets in cancer drug discovery. IKKβ is an important kinase in the canonical NF-κB pathway, which promotes survival of cancer cells and is constitutively active in number of cancers including pancreatic cancer. Inflammatory stimulus such as tumor necrosis factor-α (TNFα) is known to activate the canonical IKKβ-NF-κB pathway. Upon TNFα stimulation, serine residues 177 and 181 in the activation loop of IKKβ undergo phosphorylation resulting in activated IKKβ. Immunohistochemistry (IHC) studies showed the presence of the proinflammatory cytokine TNFα in ∼50% of surgically resected tumor specimens but in only ∼10% of corresponding normal tissues. Consistently, IHC studies by us with patient samples obtained from the UNMC rapid autopsy pancreatic cancer program showed elevated levels of phosphorylated S181 IKKβ in the tumor and liver metastases samples when compared to the stroma and ductal cells for normal pancreas. Several small molecule IKKβ inhibitors were developed by pharmaceutical industry to treat chronic inflammatory diseases. Despite complete preclinical characterization of many candidates, to date none of them has been approved by the FDA for clinical use. Nearly all the small molecule IKKβ inhibitors reported are ATP competitive. These inhibitors completely block IKKβ mediated NF-κB activity as a result chronic administration in mice leads to granulocytosis and increased susceptibility to infection-mediated death. Here we report the discovery a non-ATP competitive IKKβ inhibitor that allows transient activation but blocks the sustained activation of IKKβ mediated NF-κB activity. We present a model that has a novel-binding site, which is accessible upon activation of IKKβ and explains the observed experimental results. Our IKKβ inhibitor does not share the toxicity profile of the ATP competitive IKKβ inhibitors. In an orthotopic pancreatic tumor model mice treated with our inhibitor showed reduced tumor growth and metastasis compared to vehicle controls. We also showed that in a mantle cell lymphoma model the median survival of mice treated with our inhibitor nearly doubled when compared vehicle treated mice. Our results suggest that non-ATP competitive IKKβ inhibitors are viable lead candidates for cancer therapy. Citation Format: Sandeep Rana, Elizabeth Blowers, Amarnath Natarajan. A non-ATP competitive IKKβ inhibitor for cancer therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3645. doi:10.1158/1538-7445.AM2015-3645