Anti‐angiogenic effects of novel cyclin‐dependent kinase inhibitors with a pyrazolo[4,3‐d]pyrimidine scaffold
Anti‐angiogenic effects of novel cyclin‐dependent kinase inhibitors with a pyrazolo[4,3‐d]pyrimidine scaffold
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新型细胞周期蛋白依赖性激酶抑制剂与吡唑并[4,3ad]嘧啶支架的抗血管生成作用
DOI：
10.1111/bph.13546
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发表时间：
2016
影响因子：
7.3
通讯作者：
Zahler S
中科院分区：
文献类型：
--
作者：
Zhang S;Ulrich M;Gromnicka A;Havlíček L;Kryštof V;Jorda R;Strnad M;Vollmar AM;Zahler S
背景和目的细胞周期蛋白依赖性激酶5（CDK 5）最近成为几种肿瘤实体的有吸引力的靶点。抑制CDK 5已被证明在体外和体内具有抗血管生成作用。然而，能够在体内应用的有效的CDK 5抑制剂仍然很少。我们最近开发了一系列新的5-取代的3-异丙基-7-[4-（2-吡啶基）苄基]氨基-1（2）H-吡唑并[4，3-d]嘧啶类化合物，它们显示出抑制CDK 5的偏好，并在小鼠肝细胞癌模型中测试了它们的体外和体内活性。然后对最有效的化合物进行了迁移测试，并选择其中之一LGR 2674来评估对核碎裂、细胞周期、细胞活力和代谢活性的影响。此外，LGR 2674在试管形成试验中和在小鼠肝细胞癌模型中进行了体内试验。注射HUH 7细胞（测量体内毒性、肿瘤血管形成、肿瘤细胞增殖和肿瘤大小）。关键结果LGR 2674在增殖和迁移测定中显示出低纳摩尔范围内的EC 50。细胞毒性作用开始于50 nM，浓度不影响细胞周期。在体内，LGR 2674耐受性良好，并导致肿瘤血管密度明显降低;也抑制肿瘤细胞增殖和肿瘤生长delighted.Conclusions和ImplicationsPyrazolo[4，3-d]pyrimidine是一种新的支架内vivopotential开发有效的CDK抑制剂。这些结构是扩大我们针对各种肿瘤的药理学武器库的良好候选者。
Background and PurposeCyclin‐dependent kinase 5 (CDK5) has recently emerged as an attractive target in several tumour entities. Inhibition of CDK5 has been shown to have anti‐angiogenic effectsin vitroandin vivo. However, potent inhibitors of CDK5, which can be appliedin vivo, are still scarce. We have recently developed a new series of 5‐substituted 3‐isopropyl‐7‐[4‐(2‐pyridyl)benzyl]amino‐1(2)H‐pyrazolo[4,3‐d]pyrimidines that show a preference for inhibiting CDK5 and tested themin vitroandin vivoin a murine model of hepatocellular carcinoma.Experimental ApproachAll compounds were initially examined for effects on proliferation of HUVECs. The most potent compounds were then tested on migration, and one of them, LGR2674, was selected for assessing effects on nuclear fragmentation, cell cycle, cell viability and metabolic activity. Furthermore, LGR2674 was tested in a tube formation assay andin vivoin a murine model of hepatocellular carcinoma, induced by s.c. injection of HUH7 cells (measurement ofin vivotoxicity, tumour vascularization, tumour cell proliferation and tumour size).Key ResultsLGR2674 showed an EC50in the low nanomolar range in the proliferation and migration assays. Cytotoxic effects started at 50 nM, a concentration that did not influence the cell cycle.In vivo,LGR2674 was well tolerated and caused a clear reduction in vessel density in the tumours; also tumour cell proliferation was inhibited and tumour growth retarded.Conclusions and ImplicationsPyrazolo[4,3‐d]pyrimidine is a novel scaffold for the development of potent CDK inhibitors within vivopotential. Such structures are good candidates for broadening our pharmacological arsenal against various tumours.
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选择性细胞周期蛋白依赖性激酶抑制剂区分细胞周期和转录激酶
影响因子：
5.2
作者：
J. Węsierska;V. Kryštof
通讯作者：
V. Kryštof
影响因子：
16.6
作者：
Liebl, Johanna;Zhang, Siwei;Zahler, Stefan
通讯作者：
Zahler, Stefan
影响因子：
3.5
作者：
GLAB, N;LABIDI, B;MEIJER, L
通讯作者：
MEIJER, L
影响因子：
--
作者：
Merk H;Zhang S;Lehr T;Müller C;Ulrich M;Bibb JA;Adams RH;Bracher F;Zahler S;Vollmar AM;Liebl J
通讯作者：
Liebl J
影响因子：
50.3
作者：
Pozo K;Castro-Rivera E;Tan C;Plattner F;Schwach G;Siegl V;Meyer D;Guo A;Gundara J;Mettlach G;Richer E;Guevara JA;Ning L;Gupta A;Hao G;Tsai LH;Sun X;Antich P;Sidhu S;Robinson BG;Chen H;Nwariaku FE;Pfragner R;Richardson JA;Bibb JA
通讯作者：
Bibb JA