Cyclin-dependent kinase inhibitor therapy for hematologic malignancies.
Cyclin-dependent kinase inhibitor therapy for hematologic malignancies.
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DOI：
10.1517/13543784.2013.789859
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发表时间：
2013-06
影响因子：
6.1
通讯作者：
Grant S
中科院分区：
文献类型：
--
作者：
Bose P;Simmons GL;Grant S
细胞周期蛋白依赖性蛋白激酶(CDKs)调节细胞周期进程。某些CDK(如CDK7、CDK9)也控制细胞转录。因此，CDK是抗癌药物开发的有吸引力的靶点，因为它们的异常表达在各种恶性肿瘤中都很常见，而抑制CDK可以触发细胞凋亡。CDK抑制对抑制细胞周期和诱导细胞凋亡更为敏感，在血液系统恶性肿瘤中可能尤其有效。本文综述了目前处于不同开发阶段的多种CDK抑制剂，从泛CDK抑制剂如黄烷醇(Alvocidib)到高选择性的特定CDK抑制剂(如CDK4/6)，如PD0332991。黄烷醇诱导细胞周期停滞，并通过抑制CDK9全面抑制转录。后者可能代表其主要作用机制，通过下调多种短寿命蛋白。在早期试验中，黄烷醇在广泛的血液系统恶性肿瘤中显示出令人鼓舞的疗效。狄尼西利和PD0332991的早期结果似乎也很有希望。总体而言，CDK抑制剂单一疗法的抗肿瘤效果不大，人们正在探索合理的联合治疗，包括涉及其他靶向药物的联合治疗。虽然选择性的CDK4/6抑制可能对某些恶性肿瘤有效，但对大多数癌症可能需要广谱的CDK抑制。
Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anti-cancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction. A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising. In general, the anti-tumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad spectrum CDK inhibition will likely be required for most cancers.
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影响因子：
11.2
作者：
Chen S;Dai Y;Pei XY;Myers J;Wang L;Kramer LB;Garnett M;Schwartz DM;Su F;Simmons GL;Richey JD;Larsen DG;Dent P;Orlowski RZ;Grant S
通讯作者：
Grant S
影响因子：
11.2
作者：
Baughn, Linda B.;Di Liberto, Maurizio;Chen-Kiang, Selina
通讯作者：
Chen-Kiang, Selina
影响因子：
3
作者：
Conroy, Andrew;Stockett, David E.;Hawtin, Rachael Elizabeth
通讯作者：
Hawtin, Rachael Elizabeth
影响因子：
20.3
作者：
Byrd, John C.;Lin, Thomas S.;Grever, Michael R.
通讯作者：
Grever, Michael R.
影响因子：
11.2
作者：
Chen R;Chubb S;Cheng T;Hawtin RE;Gandhi V;Plunkett W
通讯作者：
Plunkett W