Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.
Bioorganic & medicinal chemistry. 2020 Mar 28 [Epub ahead of print]
Ikumi Kuriwaki, Minoru Kameda, Hiroyuki Hisamichi, Shigetoshi Kikuchi, Kazuhiko Iikubo, Yuichiro Kawamoto, Hiroyuki Moritomo, Yutaka Kondoh, Yasushi Amano, Yukihiro Tateishi, Yuka Echizen, Yoshinori Iwai, Atsushi Noda, Hiroshi Tomiyama, Tomoyuki Suzuki, Masaaki Hirano
Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan., Research Laboratories, Kotobuki Pharmaceutical Co., Ltd., 198 Kamigomyou Sakaki-Machi, Hanishina-Gun, Nagano 389-0697, Japan.