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直接のセル797相互作用型プテリジン-7 ((8H) - 1 誘導体は,高度に選択的で口服可能なEGFR^{L858R/T790M/C797S}阻害剤として

Wenzhe Jiang¹, Yupei He¹, Yongxiang Wang¹

¹School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.

Journal of medicinal chemistry

|August 28, 2025

まとめ

新しい薬であるM49は,非小細胞肺がん (NSCLC) でオシメルチニブに対する耐性を引き起こすEGFR変異を効果的に標的にします. この強力な阻害剤は治療抵抗を克服し患者の治療結果を改善する見込みです

科学分野:

薬剤化学
腫瘍学
薬理学について

背景:

非小細胞肺がん (NSCLC) のオシメルチニブに対する耐性獲得は,EGFR C797S変異によってしばしば引き起こされる.
このオシメルチニブに対する耐性を克服するために,新しい小分子阻害剤が必要である.

研究の目的:

EGFR変異,特にEGFR L858R/T790M/C797S (EGFR LR/TM/CS) を標的とする新しいプテリジン-7(8H) 1系阻害剤を開発する.
変異した Ser797 の残留物と周囲の水性ポケットと相互作用する阻害剤を特定する

主な方法:

プテリジン-7 ((8H) - 1の誘導体の設計と合成.
抑制活性 (IC50) とキナーゼ選択性を決定するインビトロ酵素測定法.
in vivoの薬理学的な研究
BaF3-EGFR LR/TM/CS 異種移植モデルにおける抗腫瘍効果の評価

主要な成果:

化合物M49はEGFR LR/ TM/ CSの強力な阻害を示し,IC50は18. 94nMであり,キナーゼの選択性は高い (S35=0. 005).
M49の経口投与は,Cmaxが230. 07ng/ mlと12. 14%の経口生物利用性を含む,好ましい薬動学的性質を示した.
M49は,BaF3- EGFR LR/ TM/ CS異種移植モデルにおいて,ブリガチニブよりも優れた抗腫瘍効果を示し,73. 53%対56. 05%の腫瘍成長抑制 (TGI) を達成した.

結論:

EGFR LR/TM/CS阻害剤の発見のための新しい戦略が確立されました.
Pteridin-7(8H) 1基化合物M49は,その強力なin vitroおよびin vivo活性と選択性により,NSCLCにおけるオシメルチニブ耐性を克服する有望な候補である.

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