Li Yongtao, Guo Qingxiang, Zhang Chao, Huang Zhi, Wang Tianqi, Wang Xin, Wang Xiang, Xu Guangwei, Liu Yanhua, Yang Shengyong, Fan Yan, Xiang Rong
School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China; Tianjin International S & T Cooperation Base, 94 Weijin Road, Tianjin 300071, China.
School of Medicine, Nankai University, 94 Weijin Road, Tianjin 300071, China.
Bioorg Med Chem Lett. 2017 Aug 1;27(15):3231-3237. doi: 10.1016/j.bmcl.2017.06.041. Epub 2017 Jun 15.
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 IC=12nM. 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.
设计、合成并评估了一系列同时包含LEE011和卡博替尼药效基团的新型杂化结构衍生物。令人惊讶的是，发现了一种化合物4d，它对CDK9具有高效且选择性的抑制活性，IC50 = 12 nM。它在纳摩尔水平上能有效诱导乳腺癌和肺癌细胞系凋亡。与阳性对照LEE011相比，4d与CDK9激酶ATP结合位点的分子对接显示4-(3-氟苄氧基)基团的F原子与ASN116残基之间形成了新的氢键。化合物4d可在G0/G1期和G2/M期阻断细胞周期，以防止癌细胞增殖和分化。用化合物4d治疗的裸鼠乳腺癌显示出显著的癌症抑制作用且毒性较低。综上所述，这种新型化合物4d可能是一种有前景的临床应用候选药物。
