Dual-Mechanism Allosteric Inhibitors of ERK Signaling

ERK 信号双机制变构抑制剂

• 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
• 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

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.

摘要 目前还没有FDA批准的针对ERK途径的药物，在ERK途径中，RAS 突变驱动ERK活性。长期目标是帮助开发治疗上有用的ERK 用于恶性肿瘤临床治疗的抑制剂。这个应用程序的总体目标是 表征化学和变构机理并开发一类新的共价化合物 ERK抑制剂，(II)阐明其诱导抗增殖的分子机制(S) 与FDA批准的垂直靶向ERK通路的药物联合使用的活性和(Iii) 确定患者衍生有机化合物联合治疗的体内抗肿瘤效果 和肿瘤模型。中心假设是使用共价、变构的联合疗法 可以开发出具有诱导细胞凋亡的适当效力的ERK抑制剂 并在患者衍生的肿瘤模型中促进肿瘤消退，预测临床疗效。这个 该项目的基本原理是开发一种新的化学策略来抑制ERK并确定 它的临床前治疗效果和相关机制可能提供强有力的科学 开发新的癌症治疗方法的框架。检验中心假说 通过追求两个特定的目标发生：1)ERK机制的设计和阐明 2)研究患者来源的结直肠癌中的共价ERK抑制剂 肿瘤模型。第一个目标是优化一类新的共价变构ERK抑制剂和 描述变构结合和抑制机制，以识别高度特异性的铅。第二 目的阐明RAS-和RAF-中铅抑制ERK的机制和后果 转变患者派生模型，并确定与FDA批准的 以ERK通路为靶点的药物可诱导肿瘤消退。按申请人的意见， 本申请中提出的研究具有创新性，因为它侧重于从 一类新的ERK抑制剂化合物，共价靶向ERK上的蛋白质结合位点。 这些化合物将表现出更好的药效学和阻断补偿反馈 ERK信号并诱导持久的ERK抑制以促进强大的细胞毒抗 癌症的影响。这项拟议的研究意义重大，因为预计它将为 新型ERK抑制剂继续开发和未来临床试验的科学依据 治疗。归根结底，这样的知识可以为 治疗癌症的创新疗法。