Discovery of inhibitors of ALK for the treatment of cancer

发现用于治疗癌症的 ALK 抑制剂

基本信息

批准号：
7747868
负责人：
Vicki Nienaber
金额：
$ 32.88万
依托单位：
ZENOBIA THERAPEUTICS, INC
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7747868
关键词：
Address Adverse effects Affinity American Society of Hematology Back Binding Biochemical Biological Assay Cells Cessation of life Childhood Chimeric Proteins Chronic Chronic Myeloid Leukemia Clinical Crystallization Custom Data Disease Epidermal Growth Factor Receptor Erlotinib Fibroblast Growth Factor Receptors Funding Gatekeeping Gefitinib Generations Gleevec Goals Grant Human Resources IGF1R gene Knockout Mice Laboratories Lead Libraries Ligands Literature Location Longevity Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of lung Measurable Methods Mutation Neuroblastoma Normal Cell Patients Pediatric Neoplasm Pharmaceutical Preparations Phase Phase I Clinical Trials Phase Transition Phosphotransferases Population Property Protein Tyrosine Kinase Proteins Protocols documentation Receptor Protein-Tyrosine Kinases Reporting Research Resistance Resolution Risk Role Safety Saint Jude Children&apos s Research Hospital Series Site Small Business Innovation Research Grant Specificity Structure Surface Plasmon Resonance Survival Rate System Tertiary Protein Structure Testing Therapeutic Time Toxic effect Treatment Protocols Work X-Ray Crystallography analog anaplastic lymphoma kinase anticancer treatment assay development base bcr-abl Fusion Proteins cancer therapy computerized tools design drug discovery experience improved in vivo inhibitor/antagonist interest kinase inhibitor lead series meetings mutant novel patient population posters pre-clinical programs protein complex public health relevance resistance mutation response small molecule therapy resistant three dimensional structure tool tumor tyrosine receptor

项目摘要

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.

描述（由申请人提供）：我们的目的是通过靶向受体酪氨酸激酶（RTK），变性淋巴瘤激酶（ALK）来发现新颖的安全评估候选（临床前化合物），以治疗癌症。现在证明，ALK通过表达组成型活化的融合蛋白或激活突变具有广泛的致病性参与，使该酪氨酸激酶成为药物发现研究的重要靶标。与ALK相关的癌症的许多形式很少见，但没有有效的治疗形式。这些癌症中的一些（例如神经母细胞瘤）主要是小儿肿瘤，几乎所有患者都会导致死亡。除了这些有限的人口疾病之外，ALK融合现在与肺癌的一部分有关，这种恶性肿瘤每年导致全球1180万人死亡。由于ALK在正常细胞中并未广泛表达，并且ALK基因敲除小鼠的寿命正常，并且没有明显的功能缺陷，因此预计ALK抑制剂将提供具有最小副作用的高效抗癌治疗。如果某些儿科癌症需要进行慢性治疗方案，则这种考虑将特别重要。作为额外的好处，有效和选择性的ALK抑制剂将作为重要的研究工具化合物，以帮助表征ALK在癌症中的作用以及进一步阐明ALK的正常功能。 Zenobia Therapeutics已经确定了碱的低微摩尔抑制剂，这是配体有效的药物片段。在本提案的第一阶段，Zenobia将优化这些热门单曲，完成目前未知的ALK的晶体结构，并通过基于碎片的铅发现方法（FBLD）识别其他铅序列。除了抑制WT-Alk外，Zenobia还将设计化合物，以抑制圣裘德儿童研究医院Stephen Morris博士在实验室中鉴定出的抗性突变体。在从第一阶段到第二阶段的过渡中，将选择两三个铅系列以进行额外优化，并且最能符合我们目标产品概况标准的系列将发展为先进的铅优化，以识别用于临时，IND启用研究的化合物的目标。公共卫生相关性：ALK是一种激酶，与许多癌症有关，包括许多致命且没有治疗的儿科癌症。由于小儿患者人群相对较低，因此在识别靶向ALK的临床候选者方面几乎没有完成。最近，在肺癌中观察到了ALK突变，每年导致超过100万人死亡。这增加了对ALK的兴趣。我们将与圣裘德儿童研究医院合作，找到可用于有限种群儿科癌症和肺癌的碱性抑制剂。