PLoS One. 2013 Jun 5;8(6):e65264.

Small molecule R1498 as a well-tolerated and orally active kinase inhibitor for hepatocellular carcinoma and gastric cancer treatment via targeting angiogenesis and mitosis pathways.

Chao Zhang1, Xihan Wu1, Meifang Zhang1, Liangcheng Zhu1, Rong Zhao1, Danqing Xu1, Zhaohu Lin1, Chungen Liang1, Taiping Chen2, Li Chen1, Yi Ren1, Joe Zhang1, Ning Qin1, and Xiongwen Zhang1,3*

Affiliation: 1. Roche Research and Early Development China, Shanghai, China; 2. Crown Bioscience Inc. Beijing, China; 3. Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, China.

Corresponding author: Dr. Xiongwen Zhang, present address: Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai, China

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Protein kinases play important roles in tumor development and progression. Lots of kinase inhibitors have entered into market and show promising clinical benefits.  Here we report the discovery of a novel small molecule, well-tolerated, orally active kinase inhibitor, R1498, majorly targeting both angiogenic and mitotic pathways for the treatment of hepatocellular carcinoma (HCC) and gastric cancer (GC). A series of biochemical and cell-based assays indicated that the target kinase cluster of R1498 included Aurora kinases and VEGFR2 et al. R1498 showed moderate in vitro growth inhibition on a panel of tumor cells with IC50 of micromole range. The in vivo anti-tumor efficacy of R1498 was evaluated on a panel of GC and HCC xenografts in a parallel comparison with another multikinase inhibitor sorafenib. R1498 demonstrated superior efficacy and toxicity profile over sorafenib in all test models with >80% tumor growth inhibition and tumor regression in some xenogratfts. The therapeutic potential of R1498 was also highlighted by its efficacy on three human GC primary tumor derived xenograft models with 10-30% tumor regression rate. R1498 was shown to actively inhibit the Aurora A activity in vivo, and decrease the vascularization in tumors. Furthermore, R1498 presented good in vivo exposure and therapeutic window in the pharmacokinetic and dose range finding studies. Theses evidences indicate that R1498 is a potent, well-tolerated, orally active multitarget kinase inhibitor with a unique antiangiogenic and antiproliferative profile, and provide strong confidence for further development for HCC and GC therapy.

Key words: Multikinase inhibitor, Aurora kinase, VEGFR2, Hepatocellular carcinoma, Gastric cancer

PMID: 23755206



The cure for gastric cancer (GC) and hepatocellular cancer (HCC) are still unmet medical need currently. Our site is dedicated to explore innovative therapeutics for GC and HCC prevalent in Asian population. Small molecule R1498 was discovered as multikinase inhibitor majorly targeting both VEGFR2 and Aurora kinase with reasonable selectivity over other kinases. This small molecular inhibitor (SMI) has drug-like chemical and physical properties, and passes our criteria into further determination of in vitro/in vivo potency, pharmacokinetic profiles and preliminary toxicology profiles.  The on-target profile of this SMI is validated in cell-based assay and animal model. R1498 potently inhibited tumor growth in traditional cell-line based xenograft and patient tumor derived xenogarft (PTX) models, and had superior efficacy and safety profile versus sorafenib under our assay conditions. Drs. Hanahan, D. and R.A. Weinberg proposed two important components of the six hallmarks of cancer “inducing angiogenesis” and “enabling replicative immortality” (Hallmarks of cancer: the next generation. Cell, 2011. 144(5): 646-74). R1498 targets two key steps of tumorigenesis: mitosis of cancer cells and angiogenesis by endothelial cells, thus we believe that the therapeutic strategy of targeting these two types of cells (both tumor cells and tumor vascular cells) may be of important value. The concept of targeting mitosis and angiogenesis pathways in parallel may bring novel Asian HCC and GC therapeutic approaches for development of multitarget kinase inhibitor, as well as for combinatorial therapeutics.

Xiongwen Zhang-figFigure 6. In vivo efficacy of R1498 on patient primary tumor derived xenografts. R1498 was administrated to nude mice bearing xenografts derived from three different gastric cancer patients as indicated schedule, the tumor volumes were recorded and plotted against days post inoculation (left panel), together with the body weight changes (right panel). The volume and relative body weight changes were indicated as mean6standard error (n = 10).

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