Abstract 5468: JNK-1 inhibition leads to antitumor activity in ovarian cancer

Abstract

Abstract Recent findings suggest that JNK mediates oncogenic functions in several cancer types including head and neck, gastric, and breast cancers, and melanoma, thus it may be an attractive therapeutic target. Specifically, JNK1 but not JNK2 has been shown to be important in promoting cell survival by controlling cell cycle arrest and apoptosis. Little is known about the role of JNK1 in ovarian cancer growth. Therefore, we examined the potential of JNK1 as a therapeutic target in the current study. We utilized a novel small molecule inhibitor, WBZ_4, which was designed, synthesized, and characterized by our team to curb the potential for side effects of the original compound, imatinib. WBZ_4 was designed to target both c-Kit and JNK1 while avoiding the Abl-kinase. The redesign process was based on comparing the residence time of water molecules that solvate the interfacial aligned residues across known targets of imatinib. Non-conserved sites with low residence time that had a higher propensity to dehydrate (de-wetting hot spots) were used to build blueprints for each target. By adding a methyl group to the original imatinib, we were able to attack a de-wetting hot spot present in C-Kit and JNK1 but absent from BCR-Abl, thereby increasing the specificity of the drug towards the desired targets. Here, we report on the biological effects of JNK-1 inhibition, both in vitro and in vivo using experimental models of ovarian cancer. We found a significant association of pJNK with progression free survival in the 116 epithelial ovarian cancers obtained at primary debulking therapy. WBZ_4 led to cell growth inhibition and increased apoptosis in a dose dependent fashion in four ovarian cancer cell lines. In vivo, while imatinib had no effect on tumor growth, WBZ_4 inhibited tumor growth in orthotopic murine models of ovarian cancer. The anti-tumor effect was further increased in combination with docetaxel. Silencing of JNK-1 with systemically administered siRNA led to significantly reduced tumor weights as compared to non-silencing siRNA controls, indicating that indeed the antitumor effects observed were due to JNK-1 inhibition. These studies identify JNK-1 as an attractive therapeutic target in ovarian carcinoma and that the re-designed WBZ_4 compound should be considered for further clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5468.