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Novel inhibitor for oncogenic RAS for lung cancer

肺癌致癌 RAS 的新型抑制剂

基本信息

批准号：
10312820
负责人：
Gary A Piazza
金额：
$ 39.06万
依托单位：
AUBURN UNIVERSITY AT AUBURN
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10312820
关键词：
Affect Amides Antineoplastic Agents Apoptosis Benchmarking Binding Biochemical Biological Assay Biological Availability Biological Markers Cancer Cell Growth Cancer Patient Carbamates Carcinogens Cell Cycle Arrest Cell Line Cell Proliferation Cell physiology Cells Chemicals Chemoprevention Clinic Clinical Chemoprevention Clinical Trials Code Codon Nucleotides Derivation procedure Development Disease Drug Kinetics Early treatment Epithelial Cells Formulation Future GTP Binding Genes Genetic Engineering Goals Growth Guanosine Triphosphate Phosphohydrolases Histologic Human Hydroxyl Radical In Vitro Indenes Individual Isoenzymes KRAS2 gene Lead Libraries Lung Lung Neoplasms MAP Kinase Gene Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Medical Metabolic Modeling Molecular Conformation Mutate Mutation Neoplasm Metastasis Normal tissue morphology Nucleotides Oncogenic Oncology Oral Oral Administration PI3K/AKT Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Phenols Phosphoproteins Phosphotransferases Plant Roots Prodrugs Property Proteins Proto-Oncogene Proteins c-akt RAS genes RAS inhibition Ras Inhibitor Recombinants Research Resistance Risk Running Series Signal Transduction Site Solubility Structure Synthesis Chemistry Testing Therapeutic Tobacco Tumor Cell Line Tumor Promotion Tumor Tissue Water Xenograft procedure airway epithelium analog base cancer cell cancer chemoprevention cancer therapy cell growth cigarette smoke clinical candidate cohort design drug development efficacy evaluation experimental study improved in vitro Model in vivo in vivo evaluation inhibitor insight lung cancer cell lung tumorigenesis mouse model mutant neoplastic cell novel patient derived xenograft model potential biomarker preclinical development programs prototype ras Proteins safety assessment screening small molecule small molecule inhibitor translational potential tumor tumor growth tumor progression tumor xenograft tumorigenesis

项目摘要

Project Summary/Abstract: Aberrant activation of RAS signaling is a major driver of lung cancer resulting from gain-in-function mutations in RAS genes often caused by tobacco-derived carcinogens. Constitutive activation of RAS, a GTPase, stimulates a cascade of downstream kinases to activate genes encoding for proteins essential for multiple aspects of tumorigenesis, including tumor cell proliferation, survival, and metastasis. Because KRAS is mutated during early stages of lung cancer and a major driver of tumor promotion and progression, a direct-acting, reversible, small molecule inhibitor of activated RAS holds great potential for lung cancer chemoprevention or the treatment of individuals with early stage disease. Unfortunately, previous attempts to develop RAS inhibitors were unsuccessful, in part, because of the scarcity of sites on the protein amenable to small-molecule binding. However, ongoing clinical trials of two covalent inhibitors of the relatively rare KRAS G12C mutation have validated this approach that can be expanded to inhibitors effective for a much broader spectrum of RAS mutations prevalent in lung cancer patients and other RAS-driven malignancies. A long-running medicinal chemistry program undertaking the synthesis of a focused library of indenes and screening in a cell-based assay for RAS selectivity resulted in the discovery of a novel class of RAS inhibitors. MCI-062 emerged as a lead compound following extensive chemical optimization and iterative target-directed screening. In vitro treatment of lung cancer cells harboring mutant RAS with MCI-062 inhibited growth with IC50 values as low as 2 nM, while human normal airway epithelial cells or tumor cells with low levels of activated RAS were essentially insensitive. MCI-062 was effective regardless of the RAS isozyme or mutational codon and appreciably more potent than covalent mutant-specific inhibitors of KRAS in clinical trials. Multiple lines of evidence indicate that MCI-062 inhibits tumor cell growth by directly interacting with RAS to inhibit GTP binding, blocking RAS-effector interaction, suppressing RAF/MAPK and PI3K/AKT signaling, resulting in selective apoptosis of RAS mutant tumor cells. As proof-of-concept, MCI-062 and a prototype prodrug, MCI-316, inhibited tumor growth in vivo, although further chemical optimization is needed to develop an oral formulation suitable for preclinical development. A new prodrug, MCI-1004 recently emerged from ongoing synthetic efforts with attractive drug-like properties that merit in vivo testing. We propose aims to: 1) gain further insight into how MCI- 062 selectively inhibits the growth of lung cancer cells with activated RAS; 2) synthesize new analogs and prodrugs to improve antitumor activity by oral delivery and benchmark them against MCI-1004, and 3) evaluate antineoplastic activity of MCI-1004 and a second prodrug lead in mouse models of lung cancer chemoprevention and treatment that are relevant to the clinic. The aims are structured to be conducted in parallel and designed to be translational with the goals of optimizing and selecting a drug development candidate for IND-enabling safety assessment and to gain a mechanistic rationale for biomarkers that will aid in selecting patient cohorts for future clinical trials.

项目摘要/摘要：RAS信号的异常激活是导致肺癌的主要驱动因素