Developing GRB2-PROTACs for Treatment of Lung Cancer

项目摘要 驱动受体酪氨酸激酶（RTK）的药理学靶向可以产生强烈的临床反应，但 接受表皮生长因子受体（EGFR）或间变性淋巴瘤激酶（ALK）治疗的肺癌患者 由于获得性抗性，抑制剂不可避免地经历疾病复发。更多更好的一代RTK- 靶向分子疗法已经开发出来，但获得性耐药仍然是主要和持久的临床 挑战.检查点阻断免疫疗法用于治疗肺癌，但EGFR阳性的肺癌患者 突变和ALK重排的应答率较低。我们已经绘制出了EGFR中的蛋白质网络- 突变和ALK重排肺癌，并显示生长因子结合蛋白2（GRB 2）是一个关键的致癌基因， 导致EGFR或ALK靶向治疗获得性耐药的驱动因素。共价键的最新发现 KRAS G12 C的靶向治疗为直接靶向KRAS提供了前所未有的机会。但 在KRAS突变型肺癌患者的治疗中观察到对KRAS G12 C药物的耐药性。一 全基因组分析显示了RTK信号通路的激活，GRB 2是KRAS的关键基因。 G12 C耐药。为了克服这个问题，我们将开发第一种选择性降解GRB 2的药物。 并中断GRB 2与驱动程序RTK的交互。在初步研究中，我们已经获得了一种有效的GRB 2结合剂， TX-1-124，并解析了与该化合物结合的GRB 2的晶体结构。在这个R21应用程序中，我们将 设计和合成一流的细胞可渗透蛋白水解靶向嵌合体（PROTAC）， 细胞内GRB 2，并评估新的GRB 2-PROTAC针对EGFR突变体、ALK重排和 KRAS G12 C肺癌细胞，包括对一线EGFR、ALK和KRAS G12 C靶向耐药的细胞 治疗该项目的成功将提供概念验证，即GRB 2的药理学下调 使用GRB 2-PROTAC将阻断致癌RTK信号传导并克服由RTK介导的获得性抗性 途径激活或再激活。具体目标是设计，合成和表征GRB 2- 基于GRB 2粘合剂TX-1-124的PROTAC。

Project Summary Pharmacological targeting of driver receptor tyrosine kinases (RTKs) can yield strong clinical responses, but lung cancer patients treated with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitors inevitably experience disease recurrence due to acquired resistance. More and better generations of RTK- targeting molecular therapies are developed, but still acquired resistance remains as a major and persistent clinical challenge. Checkpoint blockade immunotherapies are used to treat lung cancer, yet lung cancer patients with EGFR mutations and ALK rearrangements have low response rates. We have mapped the protein networks in EGFR- mutant and ALK-rearranged lung cancers, and shown growth factor bound protein 2 (GRB2) is a key oncogenic driver that causes acquired resistance to EGFR or ALK targeted therapies. The recent discovery of covalent targeted therapies for KRAS G12C offers an unprecedented opportunity to target KRAS directly. However, the resistance against KRAS G12C drugs is being observed in the treatment of KRAS-mutant lung cancer patients. A genome-wide analysis shows the activation of RTK signaling pathways and that GRB2 is a crucial gene for KRAS G12C drug resistance. To overcome this problem, we will develop the first drug that selectively degrades GRB2 and disrupts GRB2 interactions with driver RTKs. In preliminary studies, we have obtained a potent GRB2 binder TX-1-124 and solved the crystal structure of GRB2 bound with this compound. In this R21 application, we will design and synthesize the first-in-class cell-permeable proteolysis-targeting chimeras (PROTACs) to degrade intracellular GRB2, and evaluate potency of new GRB2-PROTACs against EGFR-mutant, ALK-rearranged, and KRAS G12C lung cancer cells including those cells resistant to first-line EGFR-, ALK- and KRAS G12C targeted therapies. The success of this project will offer the proof-of-concept that pharmacological downregulation of GRB2 using GRB2-PROTACs will block oncogenic RTK signaling and overcome acquired resistance mediated by RTK pathway activation or reactivation. The Specific Aim is the design, synthesis, and characterization of GRB2- PROTACs based on GRB2 binder TX-1-124.