A method for screening and validation of resistant mutations against kinase inhibitors.
A method for screening and validation of resistant mutations against kinase inhibitors.
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DOI：
10.3791/51984
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发表时间：
2014-12-07
期刊：
影响因子：
--
通讯作者：
Azam M
中科院分区：
文献类型：
--
作者：
Kesarwani M;Huber E;Kincaid Z;Azam M
BCR/ABL 作为慢性粒细胞白血病 (CML) 驱动癌基因的发现导致了伊马替尼的开发，事实上，伊马替尼证明了通过有效治疗 CML 患者来靶向癌症激酶的潜力。这一观察结果彻底改变了药物开发，以靶向与各种其他恶性肿瘤有关的致癌激酶，例如 EGFR、B-RAF、KIT 和 PDGFR。然而，抗激酶疗法的一个主要缺点是耐药突变的出现，导致靶标对药物的亲和力降低或丧失。了解耐药变异所采用的机制不仅有助于开发下一代抑制剂，而且还能推动使用个性化医疗的临床管理。我们报告了一种基于逆转录病毒载体的筛选策略，用于鉴定 BCR/ABL 中赋予耐药性的突变谱，这有助于开发下一代 BCR/ABL 抑制剂。我们使用 Ruxolitinib 和 JAK2 作为药物靶点对，描述了利用表达 JAK2 激酶随机突变库的小鼠 BAF3 细胞的体外筛选方法。
The discovery of BCR/ABL as a driver oncogene in chronic myeloid leukemia (CML) resulted in the development of Imatinib, which, in fact, demonstrated the potential of targeting the kinase in cancers by effectively treating the CML patients. This observation revolutionized drug development to target the oncogenic kinases implicated in various other malignancies, such as, EGFR, B-RAF, KIT and PDGFRs. However, one major drawback of anti-kinase therapies is the emergence of drug resistance mutations rendering the target to have reduced or lost affinity for the drug. Understanding the mechanisms employed by resistant variants not only helps in developing the next generation inhibitors but also gives impetus to clinical management using personalized medicine. We reported a retroviral vector based screening strategy to identify the spectrum of resistance conferring mutations in BCR/ABL, which has helped in developing the next generation BCR/ABL inhibitors. Using Ruxolitinib and JAK2 as a drug target pair, here we describe in vitro screening methods that utilizes the mouse BAF3 cells expressing the random mutation library of JAK2 kinase.
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影响因子：
3
作者：
Azam, Mohammad;Powers, John T.;Daley, George Q.
通讯作者：
Daley, George Q.
DOI：
10.1084/jem.20111694
发表时间：
2012-02-13
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Weigert O;Lane AA;Bird L;Kopp N;Chapuy B;van Bodegom D;Toms AV;Marubayashi S;Christie AL;McKeown M;Paranal RM;Bradner JE;Yoda A;Gaul C;Vangrevelinghe E;Romanet V;Murakami M;Tiedt R;Ebel N;Evrot E;De Pover A;Régnier CH;Erdmann D;Hofmann F;Eck MJ;Sallan SE;Levine RL;Kung AL;Baffert F;Radimerski T;Weinstock DM
通讯作者：
Weinstock DM
影响因子：
64.5
作者：
Azam, M;Latek, RR;Daley, GQ
通讯作者：
Daley, GQ
影响因子：
11.4
作者：
通讯作者：
--
影响因子：
3.7
作者：
Marit MR;Chohan M;Matthew N;Huang K;Kuntz DA;Rose DR;Barber DL
通讯作者：
Barber DL