8XKP

Crystal structure of human tyrosine-protein kinase Fes/Fps in complex with compound 17c

これはPDB形式変換不可エントリーです。

8XKP の概要

• エントリーDOI: 10.2210/pdb8xkp/pdb
• 分子名称: Tyrosine-protein kinase Fes/Fps, SULFATE ION, 7-[[(1R,2S)-2-azanylcyclohexyl]amino]-5-[[3-[(2S,6R)-2,6-dimethylmorpholin-4-yl]phenyl]amino]-4-oxidanylidene-3H-pyrido[3,4-d]pyridazine-8-carbonitrile, ... (4 entities in total)
• 機能のキーワード: fes, c-fes, tyrosine protein kinase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 43165.36

構造登録者

Baba, D.,Hanzawa, H. (登録日: 2023-12-23, 公開日: 2025-01-01, 最終更新日: 2025-03-19)

主引用文献

Taniguchi, T.,Yasumatsu, I.,Inagaki, H.,Baba, D.,Toyota, A.,Kaneta, Y.,Odagiri, T.,Momose, T.,Kawai, J.,Imaoka, T.,Nakayama, K.
Optimization of Novel Pyrido-pyridazinone Derivatives as FER Tyrosine Kinase Inhibitors, Leading to the Potent DS08701581.
Acs Med.Chem.Lett., 15:1010-1016, 2024

PubMed Abstract: Previously, we reported the new pyrido-pyridazinone template as a feline sarcoma-related (FER) tyrosine kinase inhibitor. Representative compound () showed strong enzyme inhibitory activity (IC50 = 0.5 nM), however, its antitumor effect was insufficient, probably due to poor solubility and resultant low bioavailability (BA). In addition, the kinase selectivity was inadequate, which may result in certain safety risks. Here, we focused on derivatization of the unoptimized C-5 position to obtain promising FER inhibitors possessing strong antitumor effects and improved selectivity, referring to their X-ray crystal structure and the docking model with FES proto-oncogene tyrosine kinase as an FER surrogate. While establishing the synthetic route of the pyrido-pyridazinone scaffold, we obtained a desired compound via our derivatization. Our optimized compound ) showed the highest class cell-free and cell activities in this template, good oral BA, and improved kinase selectivity, resulting in significant tumor growth inhibition in the Ba/F3-FER tumor model without body weight loss.

PubMed: 39015278
DOI: 10.1021/acsmedchemlett.4c00030

実験手法

X-RAY DIFFRACTION (2.05 Å)