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.
Public Health Relevance Statement: Project Summary 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.
NIH Spending Category: Cancer
Project Terms: 3-D structure; 3-dimensional structure; 3D structure; 4-(3Chloro-4-flurophenylamine)-7-methoxy-6(3-(4morpholinyl)quinazoline; 4-Quinazolinamine, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-4-morpholin] propoxy]; ALK protein; ASH; ATP[{..}]protein-tyrosine O-phosphotransferase; Address; Adverse effects; Affinity; American Society of Hematology; Anaplastic Lymphoma Kinase Ki-1; Assay; BCR-ABL; BCR-ABL Oncoprotein; BCR-ABL Protein Tyrosine Kinase; BCR/ABL; Back; Binding; Binding (Molecular Function); Bioassay; Biochemical; Biologic Assays; Biological Assay; CD246 Antigen; Cancer Treatment; Cancer of Lung; Cancers; Cells; Cessation of life; Childhood; Childhood Cancers; Childhood Neoplasm; Childhood Tumor; Chimera Protein; Chimeric Proteins; Chronic; Chronic Myeloid Leukemia; Clinical; Clinical Trials, Phase I; Crystallization; Crystallography, X-Ray; Crystallography, X-Ray Diffraction; Crystallography, X-Ray/Neutron; Crystallography, Xray; Custom; Data; Death; Disease; Disorder; Dorsum; Drugs; EC 2.7; EGFR; EPH- and ELK-Related Tyrosine Kinase; EPH-and ELK-Related Kinase; EPHA8; ERBB Protein; ERBB1; Early-Stage Clinical Trials; EphA8 Protein; Ephrin Type-A Receptor 8; Ephrin Type-A Receptor 8 Precursor; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Erlotinib; FGF-R; FGFR; Fibroblast Growth Factor Receptor Family; Fibroblast Growth Factor Receptors; Funding; Fusion Protein; Fusion Proteins, bcr-abl; Gatekeeping; Gefitinib; Generations; Genetic Alteration; Genetic Change; Genetic defect; Gleevec; Glivec; Goals; Grant; HEK3; HER1; Human Resources; IGF1R; IGF1R gene; Insulin-Like Growth Factor 1 Receptor Gene; Iressa; Kinases; Knockout Mice; Laboratories; Lead; Length of Life; Leukemia, Granulocytic, Chronic; Libraries; Ligands; Literature; Location; Longevity; Malignant Childhood Neoplasm; Malignant Childhood Tumor; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Pediatric Neoplasm; Malignant Pediatric Tumor; Malignant Tumor; Malignant Tumor of the Lung; Malignant neoplasm of lung; Manpower; Measurable; Medication; Methods; Mice, Knock-out; Mice, Knockout; Molecular Interaction; Mutation; Myelocytic Leukemia, Chronic; Myelogenous Leukemia, Chronic; Myeloid Leukemia, Chronic; N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-(4-morpholinyl)propoxy)-4-quinazolinamide; Neuroblastoma; Neuroblastoma (Schwannian Stroma-Poor); Normal Cell; Null Mouse; PTK; PTK Receptors; Patients; Pb element; Pediatric Neoplasm; Pediatric Tumor; Peptide Domain; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase Transition; Phosphotransferases; Population; Posters; Posters [Publication Type]; Programs (PT); Programs [Publication Type]; Property; Property, LOINC Axis 2; Protein Domains; Protein Tyrosine Kinase; Protein Tyrosine Kinase EEK; Proteins; Protocol; Protocols documentation; Protocols, Treatment; Pulmonary Cancer; Pulmonary malignant Neoplasm; RGM; RTK; Receptor Protein-Tyrosine Kinases; Receptor, EGF; Receptor, TGF-alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Receptors, FGF; Regimen; Reporting; Research; Resistance; Resolution; Risk; Role; SBIR; SBIRS (R43/44); Safety; Saint Jude Children's Cancer Center; Saint Jude Children's Research Hospital; Series; Single Crystal Diffraction; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Specificity; St. Jude; St. Jude Children's Cancer Center; St. Jude Children's Research Hospital; St.Jude Children's Cancer Center; St.Jude Children's Research Hospital; Structure; Surface Plasmon Resonance; Survival Rate; System; System, LOINC Axis 4; Tarceva; Tertiary Protein Structure; Testing; Therapeutic; Time; Toxic effect; Toxicities; Transforming Growth Factor alpha Receptor; Transmembrane Receptor Protein Tyrosine Kinase; Transphosphorylases; Treatment Protocols; Treatment Regimen; Treatment Schedule; Treatment Side Effects; Tyrosine Kinase; Tyrosine Kinase Growth Factor Receptor; Tyrosine Kinase Linked Receptors; Tyrosine Kinase Receptors; Tyrosine-Protein Kinase Receptor EEK; Tyrosine-Specific Protein Kinase; Tyrosylprotein Kinase; Work; X Ray Crystallographies; X-Ray Crystallography; analog; anaplastic lymphoma kinase; anticancer therapy; anticancer treatment; assay development; base; bcr-abl Fusion Proteins; c-erbB-1; c-erbB-1 Protein; cancer therapy; computational tools; computerized tools; design; designing; disease/disorder; drug discovery; drug/agent; erbB-1; erbB-1 Proto-Oncogene Protein; erbBl; experience; gatekeeper; gene product; genome mutation; heavy metal Pb; heavy metal lead; hydroxyaryl protein kinase; improved; in vivo; inhibitor; inhibitor/antagonist; interest; kinase inhibitor; lead series; life span; lifespan; lung cancer; malignancy; meetings; mutant; neoplasm/cancer; novel; patient population; pediatric; pediatric cancer; pediatric neoplasm/cancer; personnel; phase 1 study; phase 1 trial; phase I trial; posters; pre-clinical; preclinical; programs; protein complex; proto-oncogene protein c-erbB-1; protocol, phase I; public health relevance; resistance mutation; resistance to therapy; resistant; resistant to therapy; response; side effect; small molecule; social role; therapy adverse effect; therapy resistant; three dimensional structure; tool; treatment adverse effect; tumor; tyrosine receptor; tyrosyl protein kinase
