Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate
Discovery of a highly potent, selective and novel CDK9 inhibitor as an anticancer drug candidate
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发现一种高效、选择性的新型 CDK9 抑制剂作为候选抗癌药物
DOI：
10.1016/j.bmcl.2017.06.041
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发表时间：
2017-08-01
影响因子：
2.7
通讯作者：
Xiang, Rong
中科院分区：
文献类型：
--
作者：
Li, Yongtao;Guo, Qingxiang;Xiang, Rong
设计、合成并评估了一系列同时包含LEE011和卡博替尼药效团的新型杂化结构衍生物。令人惊讶的是，发现了化合物4d，它对CDK9具有高效且选择性的抑制活性，半数抑制浓度（IC50）为12纳摩尔。它能在纳摩尔水平有效诱导乳腺癌和肺癌细胞系发生凋亡。与阳性对照LEE011相比，将化合物4d与CDK9激酶的ATP结合位点进行分子对接显示，4 -（3 - 氟苄氧基）基团的氟原子与天冬酰胺116残基之间形成了一种新的氢键。化合物4d可在G0/G1期和G2/M期阻断细胞周期，从而阻止癌细胞的增殖和分化。用化合物4d处理的裸鼠乳腺癌模型显示出显著的抑癌效果且毒性较低。综上所述，这种新型化合物4d有望成为一种有潜力的临床候选药物。（C）2017爱思唯尔有限公司。保留所有权利。
A series of novel hybrid structure derivatives, containing both LEE011 and Cabozantinib pharmacophore, were designed, synthesized and evaluated. Surprisingly, a compound 4d was discovered that highly exhibited effective and selective activity of CDK9 inhibition with IC50 = 12 nM. It effectively induced apoptosis in breast and lung cancer cell lines at nanomolar level. Molecular docking of 4d to ATP binding site of CDK9 kinase demonstrated a new hydrogen bonding between F atom of 4-(3-fluorobenzyloxy) group and ASN116 residue, compared with the positive control, LEE011. The compound 4d could block the cell cycle both in G0/G1 and G2/M phase to prevent the proliferation and differentiation of cancer cells. Mice bared-breast cancer treated with compound 4d showed significant suppression of cancer with low toxicity. Taken together, this novel compound 4d could be a promising drug candidate for clinical application. (C) 2017 Elsevier Ltd. All rights reserved.