title: 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.
abstract: 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.
authors.affiliation: Roche Research and Early Development China, Shanghai, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Xihan
authors.initials: X
authors.lastname: Wu
authors.forename: Meifang
authors.initials: M
authors.lastname: Zhang
authors.forename: Liangcheng
authors.initials: L
authors.lastname: Zhu
authors.forename: Rong
authors.initials: R
authors.lastname: Zhao
authors.forename: Danqing
authors.initials: D
authors.lastname: Xu
authors.forename: Zhaohu
authors.initials: Z
authors.lastname: Lin
authors.forename: Chungen
authors.initials: C
authors.lastname: Liang
authors.forename: Taiping
authors.initials: T
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Yi
authors.initials: Y
authors.lastname: Ren
authors.forename: Joe
authors.initials: J
authors.lastname: Zhang
authors.forename: Ning
authors.initials: N
authors.lastname: Qin
authors.forename: Xiongwen
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000378:metabolism; D001569:Benzodiazepines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008938:Mitosis / Q000187:drug effects; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011720:Pyrazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; C585573:R1498 compound; D042461:Vascular Endothelial Growth Factor A; D001569:Benzodiazepines; C576917:AURKA protein, human; D064096:Aurora Kinase A