Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D.
Synthesis and Structure-Activity Relationships of Benzothienothiazepinone Inhibitors of Protein Kinase D.
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DOI：
10.1021/ml100230n
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发表时间：
2011-02-14
影响因子：
4.2
通讯作者：
Wipf, Peter
中科院分区：
文献类型：
--
作者：
Bravo-Altamirano, Karla;George, Kara M.;Frantz, Marie-Celine;LaValle, Courtney R.;Tandon, Manuj;Leimgruber, Stephanie;Sharlow, Elizabeth R.;Lazo, John S.;Wang, Q. Jane;Wipf, Peter
蛋白激酶D （PKD）是一个新的丝氨酸/苏氨酸激酶家族的成员，调节基本的细胞过程。PKD与包括癌症在内的几种疾病的发病机制有关。由于缺乏特异性抑制剂，了解PKD的生物学功能和治疗潜力的进展受到阻碍。苯并唑氮匹诺酮CID755673最近被确定为第一个有效的选择性PKD抑制剂。对这一先导结构的构效关系（SAR）的研究进一步提高了PKD1的效价。本文介绍了新型苯并噻吩噻唑平酮类似物的合成和生物学评价。我们将第二代先导物kb-NB142-70的体外PKD1抑制效力提高了10倍，并完成了向几乎同样有效的新型嘧啶支架的过渡，同时保持了出色的靶标选择性。这些有希望的结果将指导设计药理学工具来解剖PKD的功能，并为开发潜在的抗癌药物铺平道路。
Protein kinase D (PKD) is a member of a novel family of serine/threonine kinases that regulate fundamental cellular processes. PKD is implicated in the pathogenesis of several diseases, including cancer. Progress in understanding the biological functions and therapeutic potential of PKD has been hampered by the lack of specific inhibitors. The benzoxoloazepinolone CID755673 was recently identified as the first potent and selective PKD inhibitor. The study of structure-activity relationships (SAR) of this lead structure led to further improvements in PKD1 potency. We describe herein the synthesis and biological evaluation of novel benzothienothiazepinone analogs. We achieved a ten-fold increase in the in vitro PKD1 inhibitory potency for the second generation lead kb-NB142-70 and accomplished a transition to an almost equally potent novel pyrimidine scaffold, while maintaining excellent target selectivity. These promising results will guide the design of pharmacological tools to dissect PKD function and pave the way for the development of potential anti-cancer agents.
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影响因子：
3.8
作者：
Ha, Chang Hoon;Jin, Zheng Gen
通讯作者：
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影响因子：
3.6
作者：
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通讯作者：
Stoss, P
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作者：
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作者：
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