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

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.

SUBMITTER: Taniguchi T

PROVIDER: S-EPMC6511961 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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

Taniguchi Toru T Inagaki Hiroaki H Baba Daichi D Yasumatsu Isao I Toyota Akiko A Kaneta Yasuyuki Y Kiga Masaki M Iimura Shin S Odagiri Takashi T Shibata Yoshihiro Y Ueda Kiyono K Seo Maki M Shimizu Hiroki H Imaoka Tomoki T Nakayama Kiyoshi K

ACS medicinal chemistry letters 20190315 5

To obtain a new anticancer drug, we focused on FER tyrosine kinase. Starting with high-throughput screening with our in-house chemical library, compound <b>1</b>, 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 discl ...[more]

PMID: 31097992

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