Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases.
Synthesis and evaluation of novel inhibitors of Pim-1 and Pim-2 protein kinases.
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DOI：
10.1021/jm800937p
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发表时间：
2009-01-08
影响因子：
7.3
通讯作者：
Smith CD
中科院分区：
文献类型：
--
作者：
Xia Z;Knaak C;Ma J;Beharry ZM;McInnes C;Wang W;Kraft AS;Smith CD
Pim 蛋白激酶在前列腺癌以及某些形式的白血病和淋巴瘤中经常过度表达。通过筛选，将 5-(3-三氟甲基苯亚甲基)thiazolidine-2,4-dione (4a) 鉴定为 Pim-1 抑制剂，并发现它可以减弱完整细胞中标记的 Pim-1 的自身磷酸化。尽管 4a 是 ATP 的竞争性抑制剂，但对大约 50 种不同蛋白激酶的筛选表明，它对 Pim 激酶具有高选择性。 4a 与 Pim-1 的计算对接提供了先导化合物优化的模型，并合成了一系列取代的噻唑烷-2,4-二酮同系物。最有效的新化合物对 Pim-1 的 IC50 为 13 nM，对 Pim-2 的 IC50 为 2.3 µM。该系列中的其他化合物对 Pim-1 或 Pim-2 的选择性分别超过 2500 倍和 400 倍，而其他同源物对这两种同工酶基本上具有相同的效力。总体而言，这些化合物是新的 Pim 激酶抑制剂，可能为新型抗癌药物提供线索。
The Pim protein kinases are frequently overexpressed in prostate cancer and certain forms of leukemia and lymphoma. 5-(3-Trifluoromethylbenzylidene)thiazolidine-2,4-dione (4a) was identified by screening to be a Pim-1 inhibitor and was found to attenuate the autophosphorylation of tagged Pim-1 in intact cells. Although 4a is a competitive inhibitor with respect to ATP, a screen of approximately 50 diverse protein kinases demonstrated that it has high selectivity for Pim kinases. Computational docking of 4a to Pim-1 provided a model for lead optimization, and a series of substituted thiazolidine-2,4-dione congeners was synthesized. The most potent new compounds exhibited IC50s of 13 nM for Pim-1 and 2.3 µM for Pim-2. Additional compounds in the series demonstrated selectivities of more than 2500-fold and 400-fold for Pim-1 or Pim-2, respectively, while other congeners were essentially equally potent toward the two isozymes. Overall, these compounds are new Pim kinase inhibitors that may provide leads to novel anticancer agents.