Protein kinases as targets for anticancer agents: from inhibitors to useful drugs
Protein kinases as targets for anticancer agents: from inhibitors to useful drugs
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DOI：
10.1016/s0163-7258(02)00179-1
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发表时间：
2002-02-01
影响因子：
13.5
通讯作者：
Manley, PW
中科院分区：
文献类型：
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作者：
Fabbro, D;Ruetz, S;Manley, PW
在正常细胞和肿瘤细胞中，促有丝分裂信号通路的许多组分已经被鉴定，包括蛋白激酶的大家族，其作为信号转导通路的组分起作用，在不同的生物过程中发挥中心作用，例如控制细胞生长、代谢、分化和凋亡。开发选择性蛋白激酶抑制剂，可以阻断或调节由这些信号通路异常引起的疾病，被广泛认为是药物开发的一种有前途的方法。由于它们在人类癌症中的失调，蛋白激酶，如Bcr-Abl，表皮生长因子受体（HER）家族中的那些，细胞周期调节激酶如细胞周期蛋白依赖性激酶，以及参与肿瘤新血管形成的血管内皮生长因子受体激酶，是被认为是开发选择性抑制剂的主要靶标的蛋白激酶之一。这些药物发现工作已经产生了针对处于不同开发阶段（直至II/III期临床试验）的各种蛋白激酶的ATP结合位点的抑制剂和低分子量治疗剂。蛋白激酶抑制剂的三个例子进行了审查。包括靶向细胞周期激酶的低分子量化合物; HER 1/HER 2受体酪氨酸激酶的有效和选择性抑制剂，吡咯嘧啶PKI 166;和2-苯基-氨基嘧啶ST 1571（Glivec（R）Gleevec（TM）），一种针对慢性白血病（CML）中的关键作用者Bcr-Abl的靶向药物疗法。已经发现HER受体酪氨酸激酶家族的一些成员，特别是HER 1和HER 2，在多种人类肿瘤中过表达，这表明抑制HER信号传导将是一种可行的抗增殖策略。吡咯并嘧啶PKI 166被开发为具有有效的体外抗增殖和体内抗肿瘤活性的HER 1/HER 2抑制剂。基于其与疾病的明确关联，CML中的Bcr-Abl酪氨酸激酶代表了验证蛋白激酶抑制剂作为治疗剂的临床效用的理想靶点。在临床前模型中，ST 1571（Glivec（R），Gleevec（TM））显示出对Abl、c-Kit和血小板衍生生长因子受体具有选择性的有效的体外和体内抗肿瘤活性。1，111期研究表明，ST 1571具有良好的耐受性，并且在CML中显示出有希望的血液学和细胞遗传学应答，并且在e-Kit驱动的胃肠道肿瘤中显示出有希望的临床应答。(C)2002年爱思唯尔科技有限公司All rights reserved.
Many components of mitogenic signaling pathways in normal and neoplastic cells have been identified, including the large family of protein kinases, which function as components of signal transduction pathways, playing a central role in diverse biological processes, such as control of cell growth, metabolism, differentiation, and apoptosis. The development of selective protein kinase inhibitors that can block or modulate diseases caused by abnormalities in these signaling pathways is widely considered a promising approach for drug development. Because of their deregulation in human cancers, protein kinases, such as Bcr-Abl, those in the epidermal growth factor-receptor (HER) family, the cell cycle regulating kinases such as the cyclin-dependent kinases, as well as the vascular endothelial growth factor-receptor kinases involved in the neo-vascularization of tumors, are among the protein kinases considered as prime targets for the development of selective inhibitors. These drug-discovery efforts have generated inhibitors and low-molecular weight therapeutics directed against the ATP-binding site of various protein kinases that are in various stages of development (up to Phase II/III clinical trials). Three examples of inhibitors of protein kinases are reviewed. including low-molecular weight compounds targeting the cell cycle kinases; a potent and selective (R) inhibitor of the HER1/HER2 receptor tyrosine kinase, the pyrollopyrimidine PKI166; and the 2-phenyl-aminopyrimidine ST1571 (Glivec(R) Gleevec(TM)) a targeted drug therapy directed toward Bcr-Abl, the key player in chronic leukemia (CML). Some members of the HER family of receptor tyrosine kinases, in particular HER1 and HER2, have been found to be overexpressed in a variety of human tumors, suggesting that inhibition of HER signaling would be a viable antiproliferative strategy. The pyrrolo-pyrimidine PKI166 was developed as an HER1/HER2 inhibitor with potent in vitro antiproliferative and in vivo antitumor activity. Based upon its clear association with disease, the Bcr-Abl tyrosine kinase in CML represents the ideal target to validate the clinical utility of protein kinase inhibitors as therapeutic agents. In a preclinical model, ST1571 (Glivec(R), Gleevec(TM)) showed potent in vitro and in vivo antitumor activity that was selective for Abl, c-Kit, and the platelet-derived growth factor-receptor. Phase 1,111 studies demonstrated that ST1571 is well tolerated, and that it showed promising hematological and cytogenetic responses in CML and clinical responses in the e-Kit-driven gastrointestinal tumors. (C) 2002 Elsevier Science Inc. All rights reserved.