Developing GRB2-PROTACs for Treatment of Lung Cancer

项目摘要 以司机受体酪氨酸激酶(RTK)为靶点的药物可以产生强烈的临床反应，但 表皮生长因子受体(EGFR)或间变性淋巴瘤激酶(ALK)治疗肺癌 由于获得性耐药性，抑制剂不可避免地会出现疾病复发。更多更好的RTK- 靶向分子疗法已经开发出来，但获得性耐药仍然是主要的和持久的临床治疗。 挑战。检查点阻断免疫疗法用于治疗肺癌，但肺癌患者使用EGFR 突变和ALK重排的应答率很低。我们已经绘制了EGFR中的蛋白质网络- 突变和ALK重排的肺癌，并显示生长因子结合蛋白2(Grb2)是一个关键的致癌因素 导致对EGFR或ALK靶向治疗产生获得性耐药性的驱动因素。共价键的最新发现 针对KRAS G12C的靶向治疗提供了一个前所未有的机会，可以直接针对KRAS。然而， 在KRAS突变肺癌患者的治疗中观察到对KRAS G12C药物的耐药性。一个 全基因组分析表明RTK信号通路被激活，Grb2是KRAS的关键基因 对G12C耐药。为了克服这个问题，我们将开发第一种选择性降解Grb2的药物 并中断Grb2与驾驶员RTK的交互。在初步研究中，我们已经获得了一种有效的Grb2粘合剂 TX-1-124，求出了与该化合物结合的Grb2的晶体结构。在此R21应用程序中，我们将 设计合成一流的细胞透性蛋白水解靶向嵌合体(PROTAC)以降解 细胞内Grb2，并评估新的Grb2-PROTAC对EGFR突变、ALK重排和 KRAS G12C肺癌细胞，包括对一线靶向EGFR、ALK和KRAS G12C耐药的细胞 治疗。该项目的成功将提供药物下调Grb2的概念证明 使用Grb2-PROTACs将阻断致癌RTK信号转导并克服RTK介导的获得性耐药 通路激活或重新激活。具体目标是设计、合成和表征Grb2- 基于Grb2粘结剂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.