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Dual-Mechanism Allosteric Inhibitors of ERK Signaling

ERK 信号双机制变构抑制剂

基本信息

批准号：
10614057
负责人：
Kevin N Dalby
金额：
$ 52.74万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614057
关键词：
Animal Model Antineoplastic Agents Apoptotic BRAF gene Binding Binding Proteins Biological Biology Cell Death Cell Proliferation Cell Survival Cells Chemicals Clinic Clinical Treatment Clinical Trials Combined Modality Therapy Computer Models Crystallography Cysteine Development Disease remission Drug Targeting Electrons Enzyme Kinetics Evaluation Exhibits Extracellular Signal Regulated Kinases FDA approved Family Feedback Future Goals Human Induction of Apoptosis Innovative Therapy Knowledge MAP Kinase Gene MAPK1 gene MAPK3 gene Malignant Neoplasms Mediating Modality Modeling Molecular Molecular Conformation Mutation NMR Spectroscopy Nature Organoids Outcome Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Phenotype Phosphorylation Phosphotransferases Pre-Clinical Model Proteins Ras Inhibitor Ras/Raf Reaction Receptor Protein-Tyrosine Kinases Research Resistance Signal Transduction Site Testing Therapeutic Treatment Efficacy Tumor Promotion Work adduct anti-cancer cancer cell cancer type chemical kinetics clinical efficacy clinical predictive model clinically relevant cytotoxic design evidence base improved improved outcome in vivo inhibitor inhibitor therapy innovation insight kinase inhibitor loss of function melanoma member mutant novel novel strategies novel therapeutics pre-clinical recruit response standard of care tumor tumor growth tumor progression tumorigenic

项目摘要

SUMMARY There are currently no FDA-approved drugs available targeting the ERK pathway in which RAS mutations drive ERK activity. The long-term goal is to help develop therapeutically useful ERK inhibitors for the clinical treatment of malignancies. The overall objectives in this application are to (i) characterize the chemical and allosteric mechanism and develop a novel class of covalent ERK inhibitors, (ii) elucidate the molecular mechanism(s) by which they induce anti-proliferative activity in combination with FDA-approved drugs vertically targeting the ERK pathway and (iii) determine the in vivo anti-tumor efficacy of combination treatments using patient-derived organoid and tumor models. The central hypothesis is that combination therapy using covalent, allosteric inhibitors of ERK can be developed to possess suitable potency to induce apoptotic cell death and promote tumor regression in patient-derived tumor models predictive of clinical efficacy. The project's rationale is that developing a new chemical strategy to inhibit ERK and determination of its preclinical therapeutic efficacy and associated mechanisms is likely to offer a robust scientific framework for developing new cancer therapeutic approaches. Testing the central hypothesis occurs by pursuing two specific aims: 1) The design and elucidation of the mechanism of ERK recruitment site inhibitors and 2) investigating covalent ERK inhibitors in patient-derived CRC Tumor Models. The first aim is to optimize a new class of covalent allosteric ERK inhibitors and delineate allosteric binding and inhibition mechanisms to identify highly specific leads. The second aim delineates ERK inhibition's mechanisms and consequences by leads in RAS- and RAF- transformed patient-derived models and identifies agents that, combined with FDA-approved drugs targeting the ERK pathway, induce tumor regression. In the applicant's opinion, the research proposed in this application is innovative because it focuses on developing leads from a new class of ERK inhibitor compounds that covalently target a site of protein binding on ERK. These compounds will exhibit improved pharmacodynamics and block compensatory feedback signals from ERK signaling and induce durable ERK inhibition to promote robust cytotoxic anti- cancer effects. The proposed research is significant because it is expected to provide substantial scientific justification for the continued development and future clinical trials of novel ERK inhibitor therapies. Ultimately, such knowledge can offer new opportunities for the development of innovative therapies to treat cancer.

总结