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），发现新的安全性评估候选物（临床前化合物）用于治疗癌症。现在已经证明ALK通过表达组成激活的融合蛋白或激活突变在癌症中具有广泛的致病作用，使这种酪氨酸激酶成为药物发现研究的重要靶点。许多与ALK相关的癌症很罕见，但没有有效的治疗方法；其中一些癌症，如神经母细胞瘤，主要是儿童肿瘤，几乎所有患者都会死亡。除了这些有限人群疾病之外，ALK融合现在最近与肺癌的一个亚群有关，肺癌是一种恶性肿瘤，每年在全世界导致118万人死亡。由于ALK在正常细胞中不广泛表达，而且敲除ALK的小鼠寿命正常，没有明显的功能缺陷，因此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长期治疗方案，这一考虑将特别重要。作为一个额外的好处，强效和选择性的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，并进一步阐明ALK的正常功能。Zenobia Therapeutics已经确定了ALK的低微摩尔抑制剂是配体有效的药物片段。在该提案的第一阶段，Zenobia将优化这些命中，完成目前未知的ALK晶体结构，并通过基于片段的先导物发现（FBLD）方法确定其他先导物系列。除了抑制WT-ALK外，Zenobia还将设计化合物来抑制St. Jude儿童研究医院Stephen Morris博士实验室中发现的耐药突变体。在从I期到II期的过渡阶段，将选择2 - 3个先导系列进行额外的优化，最符合我们目标产品配置标准的系列将进入高级先导优化阶段，以确定用于临床前IND研究的化合物。

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.