Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation.
Hideaki Kageji, Takayuki Momose, Yasuhito Nagamoto, Noriko Togashi, Isao Yasumatsu, Yosuke Nishikawa, Kawori Kihara, Kumiko Hiramoto, Megumi Minami, Naomi Kasanuki, Takeshi Isoyama, Hiroyuki Naito
Author Information
Hideaki Kageji: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: kageji.hideaki.xa@daiichisankyo.co.jp.
Takayuki Momose: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Yasuhito Nagamoto: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Noriko Togashi: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Isao Yasumatsu: Daiichi Sankyo RD Novare Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Yosuke Nishikawa: Daiichi Sankyo RD Novare Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Kawori Kihara: Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Kumiko Hiramoto: Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Megumi Minami: Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Naomi Kasanuki: Daiichi Sankyo RD Novare Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
Takeshi Isoyama: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Hiroyuki Naito: R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Herein, we describe the discovery of the 2,4-diaminonicotinamide derivative 5j, which shows potent inhibitory activity against EGFR del19/T790M/C797S and L858R/T790M/C797S. We also report the structure-activity relationship of the 2,4-diaminonicotinamide derivatives and the co-crystal structure of 5j and EGFR del19/T790M/C797S.
Humans
Drug Resistance, Neoplasm
ErbB Receptors
Lung Neoplasms
Mutation
Protein Kinase Inhibitors
Structure-Activity Relationship
Tyrosine Kinase Inhibitors
Niacinamide
EGFR protein, human
ErbB Receptors
Protein Kinase Inhibitors
Tyrosine Kinase Inhibitors
Niacinamide
