Protein kinases play a crucial role in signal transduction as well as in cellular proliferation, differentiation, and various regulatory mechanisms. The inhibition of growth related kinases, especially tyrosine kinases, might provide new therapies for diseases such as cancer. The progress made in the crystallization of protein kinases has confirmed that the ATP-binding domain of tyrosine kinases is an attractive target for drug design. Three successful examples of drug design at Novartis using a tyrosine kinase as a molecular target are described. PKI166, a pyrrolo[2,3,-d]pyrimidine derivative, is a dual inhibitor of both the EGFR and the ErbB2 kinases. The compound entered clinical trials in 1999, based on its favorable preclinical profile: potent inhibition of EGF-mediated signalling in cells, in vivo antitumor activity in several EGFR overexpressing xenograft tumor models in nude mice, long-lasting inhibition of EGF-stimulated EGFR autophosphorylation in tumor tissue, good oral bioavailability in animals, and no prohibitive in vitro and in vivo toxicity findings. The anilino-phthalazine derivative PTK787/ZK222584 (Phase I, co-developed by Schering AG, Berlin) is a potent and selective inhibitor of both the KDR and Flt-1 kinases with interesting anti-angiogenic and pharmacokinetic properties (orally bioavailable). STI571 (Glivec, Gleevec), a phenylamino-pyrimidine derivative, is a potent inhibitor of the Abl tyrosine kinase, which is present in 95% of patients with chronic myelogenous leukemia (CML). The compound specifically inhibits proliferation of v-Abl and Bcr-Abl expressing cells (including cells from CML patients) and shows anti-tumor activity as a single agent in animal models at well-tolerated doses. Pharmacologically relevant concentrations are achieved in the plasma of animals (oral administration). Promising data from phase I and II clinical trials in CML patients (98% haematological response rate in Phase I) support the fact that the STI571 represents a new treatment modality for CML. In addition, potent inhibition of the PDGFR and c-Kit tyrosine kinases also indicates its possible clinical use in solid tumors.

中文翻译：

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酪氨酸激酶抑制剂：从合理设计到临床试验。

蛋白激酶在信号转导以及细胞增殖，分化和各种调节机制中起着至关重要的作用。与生长相关的激酶，尤其是酪氨酸激酶的抑制，可能为诸如癌症的疾病提供新的疗法。蛋白激酶结晶方面的进展已证实，酪氨酸激酶的ATP结合域是药物设计的诱人靶标。描述了使用酪氨酸激酶作为分子靶标的诺华公司药物设计的三个成功实例。PKI166是吡咯并[2,3，-d]嘧啶衍生物，是EGFR和ErbB2激酶的双重抑制剂。该化合物因其良好的临床前特性而于1999年进入临床试验：有效抑制细胞中EGF介导的信号传导，裸鼠体内几种EGFR过表达的异种移植肿瘤模型中具有体内抗肿瘤活性，对肿瘤组织中EGF刺激的EGFR自磷酸化的长期抑制，在动物中的良好口服生物利用度，并且在体外和体内没有毒性发现。苯胺-酞嗪衍生物PTK787 / ZK222584（第一阶段，由柏林先灵AG雅共同开发）是KDR和Flt-1激酶的有效和选择性抑制剂，具有令人感兴趣的抗血管生成和药代动力学特性（口服生物利用度）。STI571（Glivec，Gleevec）是一种苯基氨基-嘧啶衍生物，是Abl酪氨酸激酶的有效抑制剂，Abl酪氨酸激酶存在于95％的慢性粒细胞白血病（CML）患者中。该化合物特异性抑制表达v-Abl和Bcr-Abl的细胞（包括来自CML患者的细胞）的增殖，并在耐受良好的剂量下在动物模型中显示出作为单一药物的抗肿瘤活性。在动物血浆中达到药理学相关浓度（口服）。来自CML患者的I和II期临床试验的有希望的数据（I期的血液学应答率达到98％）支持STI571代表CML的一种新治疗方式的事实。此外，PDGFR和c-Kit酪氨酸激酶的有效抑制作用还表明其在实体瘤中的临床应用价值。来自CML患者的I和II期临床试验的有希望的数据（I期的血液学应答率达到98％）支持STI571代表CML的一种新治疗方式的事实。此外，PDGFR和c-Kit酪氨酸激酶的有效抑制作用还表明其在实体瘤中的临床应用价值。来自CML患者的I和II期临床试验的有希望的数据（I期的血液学应答率达到98％）支持STI571代表CML的一种新治疗方式的事实。此外，PDGFR和c-Kit酪氨酸激酶的有效抑制作用还表明其在实体瘤中的临床应用价值。