Development of a potent and selective FLT3 kinase inhibitor by systematic expansion of a non-selective fragment-screening hit

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• 作者：Hirofumi Nakano ; Tsukasa Hasegawa ; Riyo Imamura ; Nae Saito ; Hirotatsu Kojima ; Takayoshi Okabe ; Tetsuo Nagano ; ^{tlong@mol.f.u-tokyo.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：FLT3 ; Kinase inhibitor ; Kinase selectivity ; Fragment based drug discovery ; Acute myeloid leukemia
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：26
• 期：9
• 页码：2370-2374
• 全文大小：1725 K

文摘

A non-selective inhibitor (1) of FMS-like tyrosine kinase-3 (FLT3) was identified by fragment screening and systematically modified to afford a potent and selective inhibitor 26. We confirmed that 26 inhibited the growth of FLT-3-activated human acute myeloid leukemia cell line MV4-11. Our design strategy enabled rapid development of a novel type of FLT3 inhibitor from the hit fragment in the absence of target-structural information.