Inhibition of the ALK Receptor Kinase

ALK 受体激酶的抑制

基本信息

批准号：
6669574
负责人：
Anton Wellstein
金额：
$ 39.13万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-08-01 至 2007-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6669574
关键词：
apoptosis cell proliferation chemical models chemical registry /resource chemical structure function combinatorial chemistry computer simulation drug design /synthesis /production drug discovery /isolation enzyme activity growth factor growth factor receptors growth inhibitors kinase inhibitor laboratory mouse mitogens protein tyrosine kinase tissue /cell culture

项目摘要

DESCRIPTION (provided by applicant): The secreted growth factor pleiotrophin (PTN) acts on endothelial as well as epithelial cells and fibroblasts and it can drive tumor growth, angiogenesis, invasion as well as metastasis. Recently, we identified a receptor for PTN, the orphan tyrosine kinase anaplastic lymphoma kinase, ALK that shares homology of its kinase domain with the insulin receptor family. ALK and PTN are overexpressed in a majority of human cancers samples whilst a series of normal tissues showed no detectable receptor expression. Ribozyme-mediated reduction of ALK in glioblastoma and other tumor cells resulted in a "gene dose"-dependent reduction of xenograft tumor growth in mice and supports ALK as a valid target for drug discovery. Recently we identified small-molecule drugs that inhibit the PTN-stimulated ALK kinase in cultured cells at nanomolar concentrations and we used homology modeling to generate a 3D model of the protein with these drug candidates. We hypothesize that it will be possible to identify novel selective inhibitors and propose the following aims: Aim 1, Lead identification: We will identify in silico novel ALK kinase inhibitors using de novo drug design, library screening and virtual combinatorial library generation. The best candidates will be synthesized for the biologic assays. Aim 2, to study the inhibition of PTN-stimulated ALK kinase activity in comparison to other growth factor-induced receptor kinase activity by these candidate inhibitors. Additional molecular modeling using these data will then be used to design and optimize inhibitors. Aim 3, Lead optimization: To improve lead compounds emanating from the biologic assays by further refinement of the molecular modeling of drug / protein interaction. These new inhibitors will then be assayed against PTN-stimulated ALK kinase activity in intact cells. Aim 4: To study the efficacy and potency of the best inhibitors on cell growth. Selected inhibitors of the PTN-stimulated ALK kinase will be tested for their ability to block PTN-induced cell proliferation, anti-apoptosis and soft agar colony formation in comparison to their blockade of other growth factors. In summary, we propose the design and study of structure-based inhibitors of the PTN/ALK signaling as a close collaboration between a biology and a molecular modeling/chemistry laboratory with the purpose of discovering novel anticancer drugs.

描述（申请人提供）：分泌型生长因子多效蛋白（PTN）作用于内皮细胞、上皮细胞和成纤维细胞，可以驱动肿瘤生长、血管生成、侵袭和转移。最近，我们鉴定了 PTN 的受体，即孤儿酪氨酸激酶间变性淋巴瘤激酶 ALK，其激酶结构域与胰岛素受体家族具有同源性。 ALK 和 PTN 在大多数人类癌症样本中过度表达，而一系列正常组织未显示可检测到的受体表达。核酶介导的胶质母细胞瘤和其他肿瘤细胞中 ALK 的减少导致小鼠异种移植肿瘤生长的“基因剂量”依赖性减少，并支持 ALK 作为药物发现的有效靶标。最近，我们发现了一些小分子药物，可以在纳摩尔浓度下抑制培养细胞中 PTN 刺激的 ALK 激酶，并使用同源建模来生成这些候选药物的蛋白质 3D 模型。我们假设有可能鉴定新型选择性抑制剂，并提出以下目标：目标 1，先导化合物鉴定：我们将使用从头药物设计、文库筛选和虚拟组合文库生成，在计算机中鉴定新型 ALK 激酶抑制剂。最好的候选物将被合成用于生物测定。目标 2，研究这些候选抑制剂对 PTN 刺激的 ALK 激酶活性的抑制作用与其他生长因子诱导的受体激酶活性的抑制作用。然后，使用这些数据进行的其他分子建模将用于设计和优化抑制剂。目标 3，先导化合物优化：通过进一步完善药物/蛋白质相互作用的分子模型来改进生物测定中产生的先导化合物。然后，将在完整细胞中针对 PTN 刺激的 ALK 激酶活性对这些新抑制剂进行检测。目标 4：研究最佳抑制剂对细胞生长的功效和效力。将测试选定的 PTN 刺激的 ALK 激酶抑制剂与其他生长因子的阻断相比，其阻断 PTN 诱导的细胞增殖、抗凋亡和软琼脂集落形成的能力。总之，我们建议通过生物学和分子建模/化学实验室之间的密切合作，设计和研究基于结构的 PTN/ALK 信号抑制剂，以发现新型抗癌药物。