Synthesis, activity, and their relationships of 2,4-diaminonicotinamide derivatives as EGFR inhibitors targeting C797S mutation

  • Bioorg Med Chem Lett. 2023 Dec 6:129575. doi: 10.1016/j.bmcl.2023.129575.
Hideaki Kageji  1 ,  Takayuki Momose  2 ,  Yasuhito Nagamoto  2 ,  Noriko Togashi  2 ,  Isao Yasumatsu  3 ,  Yosuke Nishikawa  3 ,  Kawori Kihara  4 ,  Kumiko Hiramoto  4 ,  Megumi Minami  4 ,  Naomi Kasanuki  4 ,  Takeshi Isoyama  2 ,  Hiroyuki Naito  2
Affiliations
  • 1. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: [email protected].
  • 2. R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, 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: 38065292 DOI: 10.1016/j.bmcl.2023.129575
Abstract

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.

Keywords
C797S; Drug discovery; EGFR.
Products