2. Academic Validation
  3. Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity

Discovery of a potent, selective, and orally available EGFR C797S mutant inhibitor (DS06652923) with in vivo antitumor activity

  • Bioorg Med Chem. 2024 Sep 1:111:117862. doi: 10.1016/j.bmc.2024.117862.
Hideaki Kageji 1,  Takayuki Momose 2,  Masayuki Ebisawa 2,  Yusuke Nakazawa 2,  Hiroyuki Okada 2,  Noriko Togashi 2,  Yasuhito Nagamoto 2,  Wataru Obuchi 2,  Isao Yasumatsu 2,  Kawori Kihara 3,  Kumiko Hiramoto 3,  Megumi Minami 4,  Naomi Kasanuki 4,  Takeshi Isoyama 2,  Hiroyuki Naito 2,  Naoki Tanaka 2
Affiliations

Affiliations

  • 1 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: kageji.hideaki.xa@daiichisankyo.co.jp.
  • 2 Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
  • 3 Daiichi Sankyo Co., Ltd., 2716-1 Chiyodamachi, Oaza Akaiwa, Aza Kurakake, Oura, Gunma 370-0503, Japan.
  • 4 Daiichi Sankyo Co., Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan.
PMID: 39111073 DOI: 10.1016/j.bmc.2024.117862
Abstract

The C797S mutation is one of the major factors behind resistance to the third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Herein, we describe the discovery of DS06652923, a novel, potent, and orally available EGFR-triple-mutant inhibitor. Through scaffold hopping from the previously reported nicotinamide derivative, a novel biaryl scaffold was obtained. The potency was successfully enhanced by the introduction of basic substituents based on analysis of the docking study results. In addition, the difluoromethoxy group on the pyrazole ring improved the kinase selectivity by inducing steric clash with the Other kinases. The most optimized compound, DS06652923, achieved tumor regression in the Ba/F3 allograft model upon its oral administration.

Keywords

C797S; Drug discovery; EGFR.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162881
    EGFR Triple Mutation Inhibitor