Inhibitors of pro‐HGF activation overcome resistance to anti‐EGFR therapy

pro-HGF 激活抑制剂克服了抗-EGFR 治疗的耐药性

• 批准号: 9919071
• 负责人: James W Janetka
• 金额: $ 30万
• 依托单位: PROTEXASE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-17 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9919071
• 关键词: Animal Cancer Model; Animal Model; Benzamidines; Biological; CT26; Cancer Model; Cessation of life; Chemicals; Clinical Trials; Colon Carcinoma; Colorectal Cancer; Combined Modality Therapy; Cyclic Peptides; Development; Drug Kinetics; Drug Targeting; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; FDA approved; Factor Xa; Fibrinogen; Fibroblasts; Goals; Growth; HGF gene; Hematologic Neoplasms; In Vitro; Injections; Lead; Ligands; Liver Microsomes; MC38; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metastatic to; Modeling; Mus; Neoplasm Metastasis; Periodicity; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Phase; Plasma; Production; Property; Protease Inhibitor; Proteolytic Processing; Receptor Protein-Tyrosine Kinases; Resistance; ST14 gene; Series; Serine Protease; Signal Pathway; Signal Transduction; Solid Neoplasm; Testing; Therapeutic; Thrombin; Treatment Efficacy; Treatment Protocols; Urea; Work; analog; anticancer activity; autocrine; base; cancer cell; cancer therapy; cancer type; colon cancer cell line; colon cancer metastasis; colon cancer patients; colon cancer progression; design; design and construction; driving force; drug discovery; hepatocyte growth factor activator; hepsin; improved; improved outcome; in vivo; inhibitor/antagonist; lead optimization; lead series; matriptase; migration; mouse model; novel; oncology; overexpression; peptide A; peptide B; physical property; prevent; pro-hepatocyte growth factor; response; small molecule; small molecule inhibitor; targeted agent; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth; tumor microenvironment; tumor progression; unnatural amino acids

ABSTRACT Factors in the tumor microenvironment promote the growth of tumors and impact their response to therapy. Hepatocyte Growth Factor (HGF), frequently upregulated in the tumor microenvironment, activates the receptor tyrosine kinase MET expressed on cancer cells which contributes to tumor progression and confers therapeutic resistance. Because cancer cells become addicted to HGF/MET signaling, both HGF and MET are valid therapeutic targets. Although various agents have been developed to target HGF/MET signaling, there are currently no approved drugs that would inhibit HGF or block MET activity specifically. The rate-limiting step in the HGF/MET signaling is the proteolytic processing of pro-HGF to active HGF by one or more of the three serine proteases, matriptase, hepsin or HGF activator (HGFA). We have developed the first small molecule inhibitors of HGF activation which mimic the activity of the endogenous inhibitors of HGF activation, HAI-1 and HAI-2. These triplex inhibitors of hepsin, matriptase and HGFA are from two chemical series of ketobenzothiazoles (kbts) and cyclic urea benzamidines (cubs). We confirmed that these inhibitors block HGF activation and thus refer to them as synthetic HAIs (sHAIs). We have shown that sHAIs inhibit MET signaling and prevent HGF-mediated scattering, migration and survival in multiple types of cancer cells. We have shown that the lead sHAI, PTX2173, overcomes resistance to EGFR inhibitors in vitro and impedes HGF-dependent growth of lung cancer in vivo. The goal of this application is to continue lead optimization and to confirm its in vivo activity in colon cancer. We will show that PTX2173 blocks HGF-mediated growth and metastasis of colon cancer and prevents/overcomes resistance to EGFR inhibitors in vivo. Our specific aims are: Aim 1: To optimize sHAIs for improved metabolic stability and pharmacokinetic (PK) properties. To rationally design, synthesize and evaluate analogues for their HGFA, matriptase and hepsin inhibitory activity: a) cyclic peptide and b) unnatural amino acid containing kbt Inhibitors. c) To determine the in vitro metabolic stability, physical properties and in vivo PK of lead sHAIs. Aim 2: To demonstrate that PTX2173 blocks HGF-dependent tumor growth/metastasis and overcomes resistance to EGFR inhibitors in colon cancer. a) To show that PTX2173 blocks tumor growth and metastasis in two syngeneic colon cancer models that are driven by HGF, CT26 and MC38. b) To confirm that PTX2173 prevents HGF-dependent primary resistance and overcomes tumor microenvironment-mediated therapeutic resistance to EGFR targeting agents in vivo. Collectively, these studies will provide a rationale to include sHAIs into treatment regimens to block HGF- dependent tumor progression and to prevent or to overcome HGF-dependent resistance to targeted therapy, significantly improving the outcome of colon cancer patients.

抽象的 肿瘤微环境中的因素促进肿瘤生长并影响其对治疗的反应。 肝细胞生长因子 (HGF) 在肿瘤微环境中经常上调，可激活受体 酪氨酸激酶 MET 在癌细胞上表达，有助于肿瘤进展并赋予治疗作用 反抗。由于癌细胞对 HGF/MET 信号传导上瘾，因此 HGF 和 MET 均有效 治疗目标。尽管已经开发了多种针对 HGF/MET 信号传导的药物，但 目前还没有批准的药物可以专门抑制 HGF 或阻断 MET 活性。 HGF/MET 信号转导中的限速步骤是通过以下方式将 HGF 前体蛋白水解加工为活性 HGF： 三种丝氨酸蛋白酶、matriptase、hepsin 或 HGF 激活剂 (HGFA) 中的一种或多种。我们开发了 第一个 HGF 激活小分子抑制剂，模拟 HGF 内源性抑制剂的活性 激活、HAI-1 和 HAI-2。这些 hepsin、matriptase 和 HGFA 的三联抑制剂来自两种化学物质 酮苯并噻唑 (kbts) 和环脲苯甲脒 (cubs) 系列。我们证实这些抑制剂 阻断 HGF 激活，因此将其称为合成 HAI (sHAI)。我们已经证明 sHAI 抑制 MET 信号传导并防止多种类型癌细胞中 HGF 介导的散射、迁移和存活。 我们已经证明，先导 sHAI，PTX2173，在体外克服了对 EGFR 抑制剂的耐药性并阻碍了 肺癌体内 HGF 依赖性生长。该应用程序的目标是继续优化先导化合物并 确认其在结肠癌中的体内活性。我们将证明 PTX2173 可以阻断 HGF 介导的生长并 结肠癌的转移并预防/克服体内对 EGFR 抑制剂的耐药性。我们的具体目标是： 目标 1：优化 sHAI 以改善代谢稳定性和药代动力学 (PK) 特性。到 合理设计、合成并评估类似物的 HGFA、matriptase 和 hepsin 抑制活性： a) 环肽和b) 含有kbt 抑制剂的非天然氨基酸。 c) 确定先导sHAI的体外代谢稳定性、物理性质和体内PK。 目标 2：证明 PTX2173 阻断 HGF 依赖性肿瘤生长/转移并克服 结肠癌对 EGFR 抑制剂的耐药性。 a) 证明 PTX2173 在两种同基因结肠癌模型中阻断肿瘤生长和转移，这两种模型是 由 HGF、CT26 和 MC38 驱动。 b) 确认 PTX2173 预防 HGF 依赖性原发耐药并克服肿瘤 微环境介导的体内EGFR靶向药物的治疗耐药性。 总的来说，这些研究将为将 sHAI 纳入治疗方案以阻断 HGF-提供依据。 依赖的肿瘤进展并预防或克服 HGF 依赖的靶向治疗耐药性， 显着改善结肠癌患者的预后。