Discovery of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors with Antitumor Activity

  • ACS Med Chem Lett. 2019 Mar 15;10(5):737-742. doi: 10.1021/acsmedchemlett.8b00631.
Toru Taniguchi  1 ,  Hiroaki Inagaki  1 ,  Daichi Baba  2 ,  Isao Yasumatsu  3 ,  Akiko Toyota  1 ,  Yasuyuki Kaneta  1 ,  Masaki Kiga  1 ,  Shin Iimura  1 ,  Takashi Odagiri  1 ,  Yoshihiro Shibata  1 ,  Kiyono Ueda  4 ,  Maki Seo  4 ,  Hiroki Shimizu  4 ,  Tomoki Imaoka  1 ,  Kiyoshi Nakayama  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 2. Daiichi Sankyo Co., Ltd., 3-5-1 Nihonbashi-honcho, Chuo-ku, Tokyo 103-8426, Japan.
  • 3. Daiichi Sankyo RD Novare Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 4. Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 31097992 DOI: 10.1021/acsmedchemlett.8b00631
Abstract

To obtain a new Anticancer drug, we focused on FER tyrosine kinase. Starting with high-throughput screening with our in-house chemical library, compound 1, which has a pyridine moiety, was found. Referring to their X-ray crystal structure with FES proto-oncogene tyrosine kinase, as a surrogate of FER followed by chemical modification including scaffold hopping of the pyridine template, we discovered pyrido-pyridazinone derivatives with potent FER kinase inhibitory activity. Here, we disclose the structure-activity relationship on the scaffold and representative compound 21 (DS21360717), which showed in vivo antitumor efficacy in a subcutaneous tumor model.

Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128576
    DS21360717
    99.80%, FER Tyrosine Kinase Inhibitor
    target: EGFR
    Research Areas: Cancer