Abstract 941: Discovery of novel VEGFR2 and Raf-1 kinase inhibitorsuppressing MAPK signaling pathway in K-Ras mutant cancer cell-lines.
Authors: Kim Seung Yong , Lee Younho , Bang Hyungtae , Eum Kihwan , Hong Sungpyo , Nam Ky-Youb , Choi Nam Song , Kang Ju Hee , Kang Hara , Kim Kil Won , Lee Michael , Ahn Soon Kil 
Published: August 2014

Introduction: Signal transduction in the Ras-Raf-MEK-ERK (MAPK) pathway plays a key role in cell survival, growth and proliferation. The pathway is controlled by extracellular signals through receptor tyrosine kinases (RTK) and is activated by oncogenic mutations in many types of cancer. The B-Raf mutants are found in various cancers, such as melanoma, colorectal, ovarian, and prostate cancer. The Ras mutants are also found in various carcinomas including colon cancer, pancreatic cancer, non-small-cell lung cancer, and liver cancer. The mutated K-Ras gene sends continuous signals to the colorectal cancer cells, telling them to grow independent of the way ERBITUX blocks the EGFR growth signals. Especially, over 90% of detected mutations in B-Raf are a V600E which leads to constitutive kinase activity 500-fold greater than B-Raf wild type and correlates with increased malignancy. Vascular endothelial growth factor (VEGF) and its receptors have been implicated in the angiogenesis that is essential for growth and metastasis of solid tumors. Since formation of solid tumors are angiogenesis dependent, several strategies have been developed to inhibit VEGF signal transduction as part of anticancer therapy. The first VEGFR2 and Raf-1 inhibitor to enter clinical development was the multikinase inhibitor SORAFENIB, which is now approved for the treatment of patients with advanced renal cell carcinoma. More potent dual inhibitors against VEGFR2 and Raf-1 may be beneficial for patients suffering from various tumors. In this study, some of rational-designed compounds were synthesized and carried out the in vitro and in vivo studies to find more efficient VEGFR2 and Raf-1 inhibitors.

Methods: About two hundreds of compounds were designed and synthesized. in vitro assays and in vivo studies were performed to characterize the potential of VEGFR2 and Raf-1 inhibitors for solid tumors.

Results: Compound UI-162 showed strong kinase inhibition against VEGFR2 (12 nM), B-Raf V600E mutant (0.2 nM), B-Raf wildtype (2.0 nM) and Raf-1(0.6 nM). The compound showed good inhibitory effect in against malignant cells expressing K-Ras or B-Raf V600E mutant type of cell-line (SK-MEL-2 GI50: 133 nM / HCT-116 GI50: 229 nM / MDA-MB231 GI50: 278 nM / A375P GI50: 51 nM / HT29 GI50: 40 nM / COLO 205 GI50: 12 nM, respectively). In mechanism studies, the phosphorylation of MEK and ERK were suppressed by the UI-162 compound in HCT-116 cell-line. In addition, paradoxical effects were not detected compared with VEMURAFENIB. The compound had also a good anti-proliferative activity against HUVEC and showed a good oral bioavailability.

Conclusions: The results of in vitro and in vivo studies suggests that dual inhibition of VEGFR2 and Raf-1 may provide strong antitumor efficacy and that UI-162 is a promising candidate for the treatment of various human cancers harboring the K-Ras and B-Raf V600E mutation.

Citation Format: Seung Yong Kim, Younho Lee, Hyungtae Bang, Kihwan Eum, Sungpyo Hong, Ky-Youb Nam, Nam Song Choi, Ju Hee Kang, Hara Kang, Kil Won Kim, Michael Lee, Soon Kil Ahn. Discovery of novel VEGFR2 and Raf-1 kinase inhibitorsuppressing MAPK signaling pathway in K-Ras mutant cancer cell-lines. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 941. doi:10.1158/1538-7445.AM2013-941