Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer.
Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer.
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DOI：
10.1038/bjc.2016.238
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发表时间：
2016-09-06
影响因子：
8.8
通讯作者：
Cano, Celine
中科院分区：
文献类型：
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作者：
Beale, Gary;Haagensen, Emma J.;Thomas, Huw D.;Wang, Lan-Zhen;Revill, Charlotte H.;Payne, Sara L.;Golding, Bernard T.;Hardcastle, Ian R.;Newell, David R.;Griffin, Roger J.;Cano, Celine
磷脂酰肌醇-3-激酶/哺乳动物靶向雷帕霉素(PI3K/mTOR)通路在人类癌症中普遍处于失控状态，因此许多PI3K和mTOR抑制剂已被开发出来，并已进入临床试验。同样，CDK也被作为抗癌药物的靶点进行了研究。我们已经合成并表征了一系列6-氨基嘧啶类化合物，它们是从抑制PI3K和/或mTOR和/或CDK2的激酶筛选中鉴定出来的。在HCT116和HT29结直肠癌细胞系中进行了激酶抑制、肿瘤细胞生长、细胞周期分布、细胞毒性和信号转导实验，并对HT29进行了体内疗效研究。带有O4-环己基甲基取代基和C-5-亚硝基或氰基(1，2，5)的2，6-二氨基嘧啶可引起细胞周期时相改变，并抑制细胞生长(GI50<；20 μM)。化合物1对CDK2(IC_(50)=0.1 nM)和PI3K有明显的抑制作用，且在生长抑制浓度下具有细胞毒性。与激酶抑制数据一致，化合物1在GI50浓度下降低了磷酸化Rb和磷酸化RS6。联合应用NU6102(CDK2抑制剂)和Pickilsib(GDC-0941；PAN-PI3K抑制剂)可协同抑制HT29细胞的生长，增强体外对HT29细胞的杀伤作用和体内抑制HT29肿瘤生长的作用。这些研究确定了一系列新的CDK2/PI3K混合抑制剂，并证明了CDK2和PI3K的双重靶向可以导致增强的抗肿瘤活性。
The phosphatidylinositol-3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway is commonly deregulated in human cancer, hence many PI3K and mTOR inhibitors have been developed and have now reached clinical trials. Similarly, CDKs have been investigated as cancer drug targets. We have synthesised and characterised a series of 6-aminopyrimidines identified from a kinase screen that inhibit PI3K and/or mTOR and/or CDK2. Kinase inhibition, tumour cell growth, cell cycle distribution, cytotoxicity and signalling experiments were undertaken in HCT116 and HT29 colorectal cancer cell lines, and in vivo HT29 efficacy studies. 2,6-Diaminopyrimidines with an O4-cyclohexylmethyl substituent and a C-5-nitroso or cyano group (1,2,5) induced cell cycle phase alterations and were growth inhibitory (GI50<20 μM). Compound 1, but not 2 or 5, potently inhibits CDK2 (IC50=0.1 nM) as well as PI3K, and was cytotoxic at growth inhibitory concentrations. Consistent with kinase inhibition data, compound 1 reduced phospho-Rb and phospho-rS6 at GI50 concentrations. Combination of NU6102 (CDK2 inhibitor) and pictilisib (GDC-0941; pan-PI3K inhibitor) resulted in synergistic growth inhibition, and enhanced cytotoxicity in HT29 cells in vitro and HT29 tumour growth inhibition in vivo. These studies identified a novel series of mixed CDK2/PI3K inhibitors and demonstrate that dual targeting of CDK2 and PI3K can result in enhanced antitumour activity.
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影响因子：
3.7
作者：
Haagensen EJ;Thomas HD;Wilson I;Harnor SJ;Payne SL;Rennison T;Smith KM;Maxwell RJ;Newell DR
通讯作者：
Newell DR
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
20.3
作者：
Condliffe, AM;Davidson, K;Hawkins, PT
通讯作者：
Hawkins, PT
影响因子：
45.3
作者：
Lin, Thomas S.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
2.7
作者：
Mesguiche, V;Parsons, RJ;Hardcastle, IR
通讯作者：
Hardcastle, IR