Development of a first-in-class mEGFR dimerization inhibitor

开发一流的 mEGFR 二聚化抑制剂

• 批准号: 10778673
• 负责人: THEODORE S LAWRENCE
• 金额: $ 33.35万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-03 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10778673
• 关键词: Address; Advanced Development; Area; Binding; Biodistribution; Biological Availability; Cancer Patient; Cancer cell line; Cell Death; Cell Line; Cell Survival; Cells; Chronic; Clinical; Clinical Research; Clinical effectiveness; Data; Development; Diagnosis; Dimerization; Dose; Drug Exposure; Drug Kinetics; Effectiveness; Epidermal Growth Factor Receptor; Exposure to; Frequencies; Future; Generations; Genes; Goals; Immunocompetent; In Vitro; Knowledge; Luciferases; Lung Neoplasms; Malignant neoplasm of lung; Methods; Modeling; Monitor; Mus; Mutate; Mutation; Non-Small-Cell Lung Carcinoma; Normal Cell; Null Lymphocytes; Oncogenic; Oral; Oral Administration; Organ; Patient-Focused Outcomes; Patients; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Phosphotransferases; Plasma; Positron-Emission Tomography; Probability; Progression-Free Survivals; Protein Tyrosine Kinase; Proteins; Receptor Protein-Tyrosine Kinases; Regimen; Research Design; Resistance; Resistance development; Safety; Schedule; Series; Specificity; Statistical Models; Study models; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; Tyrosine Kinase Inhibitor; Xenograft Model; Xenograft procedure; cancer cell; cancer imaging; cancer therapy; chemotherapy; clinically relevant; design; efficacy evaluation; improved outcome; in vivo; in vivo evaluation; inhibitor; inhibitor therapy; lung cancer cell; lung xenograft; mouse model; mutant; neoplastic cell; novel; patient derived xenograft model; pharmacokinetics and pharmacodynamics; pre-clinical; protein expression; receptor; receptor expression; refractory cancer; resistance mutation; response; small molecule; targeted agent; therapy resistant; treatment effect; treatment response; tumor; tumor progression

Background: Lung cancers are often driven by mutant epidermal growth factor receptor (mtEGFR). While EGFR tyrosine kinase activity inhibitors (TKI) have shown effectiveness, within 9-13 months all patients develop resistance including to 3rd generation TKI - Osimertinib. These patients do not have any approved therapy options, therefore, there is an urgent need to develop a novel agent that functions independently of kinase function. DGD1202, a first-in-class, novel, orally bioavailable, small molecule that inhibits EGFR dimerization, induces degradation of EGFR and selectively kills TKI resistant NSCLC tumors. Objective: We and others have shown that the degradation of mutant EGFR protein has a profound effect on cancer cell survival. Thus, we hypothesized that a drug which induces degradation of mtEGFR independent of the ATP binding domain will result in selective activity. Our objective is to evaluate the therapeutic potential of DGD1202 in a panel of lung cancer cells lines, xenografts, and PDXs derived from lung cancer patients containing mtEGFR who have undergone treatment with a TKI. Specific Aims: We propose to evaluate the specificity and potency of DGD1202 against TKI-resistant lung cancer cells and xenografts. Aim 1 is to determine the in vitro efficacy of DGD1202 against a panel of EGFR driven, including osimertinib-resistant, cancer cell lines relative to normal cells. Aim 2 is to conduct in vivo pharmacokinetic (PK) and pharmacodynamic (PD) analyses to assess drug exposure and determine the effect on the target. Aim 3 is to determine the overall therapeutic efficacy and long-term safety of DGD1202 in vivo. We hypothesize that treatment with DGD1202 will induce EGFR degradation preferentially in tumor cells driven by mtEGFR and that EGFR degradation will correlate with the overall response. Study Design: We will screen DGD1202 alongside osimertinib in a series of lung cancer lines. The resulting response will be then correlated with effect on EGFR degradation. We also propose to determine in vivo PK and PD studies both with a single and with fractionated dosing to determine the optimum bioavailability. Using the optimized dose and schedule, we will assess effects on EGFR protein against a panel mtEGFR-driven and osimertinib resistant lung cancer xenograft and PDX models. The long-term safety will be assessed in immune competent mice. Standard statistical models will be used to compare the response to treatment and how it correlates with effects on EGFR. Impact: We anticipate that our approach will open a new way to target EGFR and, more broadly, to develop therapeutics to selectively target mutated proteins to degradation. The knowledge gained from in vivo tumor models will provide a rationale for the use of this class of molecules in future clinical studies.

背景：肺癌通常由突变型表皮生长因子受体（mtEGFR）驱动。而 EGFR酪氨酸激酶活性抑制剂（TKI）已显示出有效性，所有患者在9-13个月内 产生耐药性，包括对第三代TKI -奥希替尼的耐药性。这些患者没有任何批准的 因此，迫切需要开发一种新的药物，其功能独立于治疗选择。 激酶功能DGD 1202，一种新型口服生物可利用小分子，可抑制EGFR 二聚化诱导EGFR降解并选择性杀死TKI抗性NSCLC肿瘤。 目的：我们和其他人已经表明，突变型EGFR蛋白的降解对EGFR的表达有深远的影响。 癌细胞存活率因此，我们假设一种诱导mtEGFR降解的药物， ATP结合结构域将导致选择性活性。我们的目标是评估 一组肺癌细胞系、异种移植物和源自肺癌患者的PDX中的DGD 1202 接受过TKI治疗的患者。 具体目的：我们建议评价DGD 1202对TKI耐药肺的特异性和效力。 癌细胞和异种移植物。目的1是确定DGD 1202对一组EGFR的体外疗效 相对于正常细胞，包括奥西替尼耐药的癌细胞系。目的2是在体内进行 药代动力学（PK）和药效学（PD）分析，以评估药物暴露并确定效应 在目标上。目的3是确定DGD 1202在体内的总体疗效和长期安全性。 我们假设用DGD 1202治疗将在肿瘤细胞中优先诱导EGFR降解， 通过mtEGFR，EGFR降解将与总体反应相关。 研究设计：我们将在一系列肺癌细胞系中筛选DGD 1202和奥希替尼。所得 然后将反应与对EGFR降解的影响相关联。我们还建议测定体内PK 以及单次和分次给药的PD研究，以确定最佳生物利用度。使用 优化的剂量和时间表，我们将评估对EGFR蛋白的影响， 奥希替尼抗性肺癌异种移植物和PDX模型。将在免疫组化中评估长期安全性。 有能力的老鼠将使用标准统计模型比较治疗反应以及 与对EGFR的影响相关。 影响：我们预计，我们的方法将开辟一种新的方式来靶向EGFR，更广泛地说， 选择性靶向突变蛋白质以降解的治疗剂。从体内肿瘤获得的知识 模型将为在未来的临床研究中使用这类分子提供理论基础。