Identification and characterization of a novel integrin-linked kinase inhibitor.
Identification and characterization of a novel integrin-linked kinase inhibitor.
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DOI：
10.1021/jm2007744
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发表时间：
2011-09-22
影响因子：
7.3
通讯作者：
Chen, Ching-Shih
中科院分区：
文献类型：
--
作者：
Lee, Su-Lin;Hsu, En-Chi;Chou, Chih-Chien;Chuang, Hsiao-Ching;Bai, Li-Yuan;Kulp, Samuel K.;Chen, Ching-Shih
整合素连接激酶（ILK）因其在促进肿瘤发生和肿瘤进展中的作用而成为癌症治疗的相关靶点。通过筛选内部重点化合物库，我们确定 N-Mmethyl-3-(1-(4-(piperazin-1-yl)苯基)-5-(4′-(三氟甲基)-[1,1′-联苯]-4-yl)-1H-pyrazol-3-yl)propanamide (22) 是一种新型 ILK 抑制剂（IC50，0.6 μM）， 在体外对一组前列腺癌细胞系和乳腺癌细胞系表现出高效力（IC50，1 – 2.5 μM），而正常上皮细胞不受影响。化合物 22 促进 Akt Ser-473 和其他 ILK 靶标（包括糖原合酶激酶 3β 和肌球蛋白轻链）的去磷酸化。此外，22 抑制 PC-3 细胞中转录/翻译因子 YB-1 及其靶标 HER2 和 EGFR 的表达，这可以通过组成型活性 ILK 的稳定表达来挽救。有证据表明 22 诱导自噬和细胞凋亡，这两者都是其抗增殖活性的组成部分。总之，这种广泛的机制构成了 22 在癌症治疗中的治疗潜力，这通过其作为单一口服药物抑制 PC-3 异种移植肿瘤生长的体内功效得以体现。
Integrin-linked kinase (ILK) represents a relevant target for cancer therapy in light of its role in promoting oncogenesis and tumor progression. Through the screening of an in-house focused compound library, we identified N-Methyl-3-(1-(4-(piperazin-1-yl)phenyl)-5-(4′-(trifluoromethyl)-[1,1′-biphenyl]-4-yl)-1H-pyrazol-3-yl)propanamide (22) as a novel ILK inhibitor (IC50, 0.6 μM), which exhibited high in vitro potency against a panel of prostate and breast cancer cell lines (IC50, 1 – 2.5 μM), while normal epithelial cells were unaffected. Compound 22 facilitated the dephosphorylation of Akt at Ser-473 and other ILK targets, including glycogen synthase kinase-3β and myosin light chain. Moreover, 22 suppressed the expression of the transcription/translation factor YB-1 and its targets HER2 and EGFR in PC-3 cells, which could be rescued by the stable expression of constitutively active ILK. Evidence indicates that 22 induced autophagy and apoptosis, both of which were integral to its antiproliferative activity. Together, this broad spectrum of mechanisms underlies the therapeutic potential of 22 in cancer treatment, which is manifested by its in vivo efficacy as a single oral agent in suppressing PC-3 xenograft tumor growth.
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DOI：
10.1083/jcb.150.4.861
发表时间：
2000-08-21
期刊：
The Journal of cell biology
影响因子：
--
作者：
Huang Y;Li J;Zhang Y;Wu C
通讯作者：
Wu C
影响因子：
3.5
作者：
Ito, R;Oue, N;Yasui, W
通讯作者：
Yasui, W
DOI：
10.1073/pnas.060579697
发表时间：
2000-03-28
影响因子：
11.1
作者：
Persad, S;Attwell, S;Dedhar, S
通讯作者：
Dedhar, S
影响因子：
4.8
作者：
Deng, JT;Van Lierop, JE;Walsh, MP
通讯作者：
Walsh, MP
影响因子：
3.7
作者：
Eke, Iris;Leonhardt, Franziska;Cordes, Nils
通讯作者：
Cordes, Nils