Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors
Therapeutic potential of investigational CHK-1 inhibitors for the treatment of solid tumors
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DOI：
10.1080/13543784.2017.1360275
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发表时间：
2017-01-01
影响因子：
6.1
通讯作者：
Mahadevan, Daruka
中科院分区：
文献类型：
--
作者：
Babiker, Hani M.;McBride, Ali;Mahadevan, Daruka
简介：几十年来，靶向DNA修复途径的癌症治疗仅包括化疗和放疗。然而，在过去的十年中，DNA修复过程的知识的提高为开发消除DNA修复信号的新型靶向药物铺平了道路。检查点激酶抑制剂是令人兴奋的分子，在实体瘤和血液系统恶性肿瘤的治疗中有希望。在此，我们讨论了这类molecules.Areas覆盖的临床前和临床研究：在这篇综述中，我们讨论了检查点激酶1（CHK-1）在DNA修复中的作用，并提供了一个全面的总结临床前和早期阶段的临床试验与CHK-1抑制剂。我们还提供了CHK-1抑制剂与CHK-1结合的分子结构基础。专家意见：临床前和早期临床研究的数据表明，这类分子与抗代谢药物联合治疗实体瘤和血液系统恶性肿瘤时具有潜在的疗效。此外，在p53或BRCA突变的肿瘤中，将这类分子与PARP抑制剂、铂化疗或放射治疗相结合可能具有附加作用。上述组合的安全性需要在正在进行的临床试验中进行密切评估。
Introduction: For several decades' cancer treatment targeting DNA repair pathways incorporated both chemo- and radiotherapy only. However, over the last decade improved knowledge of DNA repair processes has paved the way for the development of novel targeted drugs abrogating DNA repair signaling. Checkpoint kinase inhibitors are exciting molecules and hold promise in the treatment of both solid and hematologic malignancies. Herein, we discuss preclinical and clinical studies with this class of molecules.Areas covered: In this review, we discuss the role of check point kinase 1 (CHK-1) in DNA repair and provide a comprehensive summary of pre-clinical and early phase clinical trials with CHK-1 inhibitors. We also provide molecular structural basis of CHK-1inhibitors binding to CHK-1.Expert opinion: Available data from both pre-clinical and early clinical studies illustrates potential efficacy of this class of molecules when combined with antimetabolites in treating both solid and hematologic malignancies. In addition, there might be an additive role in combining this class of molecules to PARP inhibitors, platinum chemotherapy, or radiation therapy in p53 or BRCA mutated tumors. The safety of the aforementioned combination needs to be closely evaluated in the ongoing clinical trials.