Discovery of inhibitors of ALK for the treatment of cancer

点击翻译按钮获取中文摘要

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.