Discovery of inhibitors of ALK for the treatment of cancer

描述(由申请人提供)：我们的目标是通过靶向受体酪氨酸激酶(RTK)、间变性淋巴瘤激酶(ALK)来发现治疗癌症的新的安全性评估候选者(临床前化合物)。现在已经证明，ALK通过表达结构性激活的融合蛋白或激活突变而广泛参与癌症的致病过程，使这种酪氨酸激酶成为药物发现研究的重要靶点。与ALK相关的许多癌症形式很罕见，但没有有效的治疗形式；其中一些癌症，如神经母细胞瘤，主要是儿科肿瘤，导致几乎所有患有ALK的患者死亡。除了这些有限人群的疾病，ALK融合最近还与肺癌的一种亚型有关，肺癌是一种恶性肿瘤，每年导致全球118万人死亡。由于ALK在正常细胞中不广泛表达，并且ALK基因敲除小鼠的正常寿命和没有可察觉的功能缺陷，ALK抑制剂有望提供副作用最小的高效抗癌治疗；如果某些儿童癌症需要慢性治疗方案，这一考虑将特别重要。作为一个额外的好处，有效的和选择性的ALK抑制剂将作为重要的研究工具化合物，帮助表征ALK在癌症中的作用以及进一步阐明ALK的正常功能。泽诺比亚治疗公司已经确定了低微摩尔的ALK抑制剂，这些药物是配体高效的药物片段。在这项提议的第一阶段，Zenobia将优化这些点击，完成目前未知的ALK的晶体结构，并通过基于片段的铅发现(FBLD)方法识别额外的铅系列。除了抑制WT-ALK，Zenobia还将设计化合物来抑制圣裘德儿童研究医院斯蒂芬·莫里斯博士的实验室中发现的耐药突变。在从第一阶段过渡到第二阶段时，将选择两到三个铅系列进行进一步优化，最符合我们目标产品简介标准的系列将进入高级铅优化，以实现识别化合物用于临床前IND支持研究的目标。 与公共卫生相关：ALK是一种与许多癌症有关的激酶，包括一些致命且无法治疗的儿科癌症。由于儿科患者人口相对较低，因此在确定针对ALK的临床候选对象方面几乎没有完成工作。最近，在肺癌中发现了ALK突变，每年导致100多万人死亡。这增加了人们对ALK的兴趣。我们将与圣犹大儿童研究医院合作，寻找可用于有限人群儿童癌症和肺癌的ALK抑制剂。

DESCRIPTION (provided by applicant): Our aim is to discover novel safety assessment candidates (pre-clinical compounds) for the treatment of cancer by targeting the receptor tyrosine kinase (RTK), anaplastic lymphoma kinase (ALK). It is now proven that ALK has a widespread pathogenic involvement in cancer through the expression of either constitutively activated fusion proteins or activating mutations, making this tyrosine kinase an important target for drug discovery research. Many of the forms of cancer associated with ALK are rare but have no effective forms of treatment available; some of these cancers such as neuroblastoma are primarily pediatric tumors and result in death for nearly all patients with them. Beyond these limited-population diseases, ALK fusions have now recently been associated with a subset of lung cancer, a malignancy that results in 1.18 million deaths per year worldwide. Since ALK is not broadly expressed in normal cells and ALK knockout mice have a normal life span and no discernible functional deficits, ALK inhibitors are expected to provide highly effective anticancer treatments with minimal side effects; this consideration will be of especial importance should a chronic treatment regimen be required for certain pediatric cancers. As an additional benefit, potent and selective ALK inhibitors will serve as important research tool compounds to assist in the characterization of the role of ALK in cancer as well as for further elucidation of the normal functions of ALK. Zenobia Therapeutics has identified low micromolar inhibitors of ALK that are ligand efficient fragments-of-drugs. During Phase I of this proposal, Zenobia will optimize these hits, complete the crystal structure of ALK, which is currently unknown, and identify additional lead series through the method of Fragment-Based Lead Discovery (FBLD). In addition to inhibiting WT-ALK, Zenobia will design compounds to inhibit resistant mutants identified in the laboratory of Dr. Stephen Morris of St. Jude Children's Research Hospital. At the transition from Phase I to Phase II, two-three lead series will be chosen for additional optimization and the series that best meets the criteria of our target product profile, will progress into advanced lead optimization towards the goal of identifying compounds for pre-clinical, IND enabling studies. PUBLIC HEALTH RELEVANCE: ALK is a kinase that has been implicated in a number of cancers including a number of pediatric cancers which are fatal and have no treatment. Because the pediatric patient population is relatively low, little work has been completed in identifying a clinical candidate that targets ALK. Recently, ALK mutations have been observed in lung cancer which results in over 1 million deaths per year. This has increased interest in ALK. We will be working with St. Jude Children's Research Hospital to find ALK inhibitors that may be used for limited population pediatric cancers and for lung cancer.