2. Academic Validation
  3. Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2

Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2

  • Bioorg Med Chem. 2020 May 15;28(10):115453. doi: 10.1016/j.bmc.2020.115453.
Ikumi Kuriwaki 1,  Minoru Kameda 2,  Hiroyuki Hisamichi 2,  Shigetoshi Kikuchi 2,  Kazuhiko Iikubo 2,  Yuichiro Kawamoto 2,  Hiroyuki Moritomo 2,  Yutaka Kondoh 2,  Yasushi Amano 2,  Yukihiro Tateishi 2,  Yuka Echizen 2,  Yoshinori Iwai 3,  Atsushi Noda 3,  Hiroshi Tomiyama 3,  Tomoyuki Suzuki 2,  Masaaki Hirano 2
Affiliations

Affiliations

  • 1 Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: ikumi.kuriwaki@astellas.com.
  • 2 Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
  • 3 Research Laboratories, Kotobuki Pharmaceutical Co., Ltd., 198 Kamigomyou Sakaki-Machi, Hanishina-Gun, Nagano 389-0697, Japan.
PMID: 32278710 DOI: 10.1016/j.bmc.2020.115453
Abstract

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/KDR/Flk-1) 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/KDR/Flk-1.

Keywords

Fibroblast growth factor receptor 3; Kinase selectivity; Structure activity relationships; Structure-based drug design; Vascular endothelial growth factor receptor 2; X-ray crystal structure.

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