Development of a first-in-class mEGFR dimerization inhibitor

背景：肺癌通常由突变的表皮生长因子受体(MtEGFR)引起。而当 EGFR酪氨酸激酶活性抑制剂(TKI)已经显示出有效性，在9-13个月内所有患者 产生包括对第三代TKI-Osimertinib的抗性。这些患者没有任何经批准的 因此，迫切需要开发一种新的药物，其作用独立于 激活素的功能。DGD1202，一种一流的新型口服生物利用小分子，可抑制EGFR 二聚化，诱导EGFR的降解，选择性地杀死对TKI耐药的NSCLC肿瘤。 目的：我们和其他人已经证明，突变的EGFR蛋白的降解对 癌细胞存活。因此，我们假设，一种诱导mtEGFR降解的药物独立于 ATP结合域将导致选择性活性。我们的目标是评估其治疗潜力。 肺癌患者来源的肺癌细胞系、异种移植瘤和PDX中的DGD1202 含有接受过TKI治疗的mtEGFR。 具体目的：我们建议评估DGD1202对TKI耐药肺的特异性和有效性 癌细胞和异种移植。目的1确定DGD1202对一组EGFR的体外疗效 驱动，包括对奥西美替尼耐药的癌细胞株，相对于正常细胞。目标2是在体内进行 药代动力学(PK)和药效学(PD)分析，以评估药物暴露和确定效果 在目标上。目的3在体内测定DGD1202的总体疗效和长期安全性。 我们假设DGD1202治疗将优先诱导肿瘤细胞中EGFR的降解 通过mtEGFR，EGFR的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查DGD1202和奥西美替尼。由此产生的 然后，反应将与对EGFR降解的影响相关联。我们还建议在体内测定PK PD研究包括单次给药和分次给药，以确定最佳生物利用度。vbl.使用 在优化的剂量和时间表下，我们将评估mtEGFR驱动的和 奥西美替尼耐药肺癌移植瘤和PDX模型。长期安全性将在免疫系统中进行评估 有能力的老鼠。标准的统计模型将被用来比较对治疗的反应和如何 与对EGFR的影响有关。 影响：我们预计我们的方法将打开一种新的方式来瞄准EGFR，更广泛地说，开发 治疗选择性地以突变蛋白为目标进行降解。从体内肿瘤中获得的知识 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。

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.