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 肿瘤微环境的因素促进了肿瘤的生长并影响其对治疗的反应。 在肿瘤微环境中经常上调的肝细胞生长因子（HGF）激活受体 在癌细胞上表达的酪氨酸激酶有助于肿瘤进展并赋予治疗 反抗。由于癌细胞沉迷于HGF/MET信号传导，因此HGF和MET都是有效的 治疗靶标。尽管已经开发出各种代理来靶向HGF/MET信号，但仍有 目前尚无批准会抑制HGF或阻止MET活动的药物。 HGF/MET信号传导中的速率限制步骤是Pro-HGF对主动HGF的蛋白水解处理 三种丝氨酸蛋白酶，即基质酶，hepsin或HGF激活剂（HGFA）中的一个或多个。我们已经发展了 HGF激活的第一个小分子抑制剂，该抑制剂模仿HGF的内源性抑制剂的活性 激活，HAI-1和HAI-2。这些三环蛋白，曲霉酶和HGFA的三环抑制剂来自两种化学物质 系列酮苯甲唑（KBTS）和环状尿素苯甲胺（幼崽）。我们确认这些抑制剂 阻止HGF激活，因此将其称为合成HAI（SHAI）。我们已经表明shais抑制了 在多种类型的癌细胞中，信号传导并防止HGF介导的散射，迁移和存活。 我们已经表明，铅shai PTX2173在体外和阻碍了对EGFR抑制剂的耐药性 肺癌在体内的HGF依赖性生长。该应用程序的目的是继续领导优化和 确认其在结肠癌中的体内活性。我们将证明PTX2173阻止了HGF介导的增长和 结肠癌的转移并防止/克服体内EGFR抑制剂的抗性。我们的具体目的是： 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，合成和评估其HGFA，Matriptase和Hepsin抑制活性的类似物： a）环状肽和b）含有KBT抑制剂的非天然氨基酸。 c）确定体外代谢稳定性，物理特性和铅shais的体内PK。 目标2：证明PTX2173阻止了HGF依赖性肿瘤的生长/转移并克服 对结肠癌中EGFR抑制剂的抗性。 a）表明PTX2173阻止了两个合成性结肠癌模型中的肿瘤生长和转移 由HGF，CT26和MC38驱动。 b）确认PTX2173可防止HGF依赖性的原发性抗性并克服肿瘤 微环境介导的对EGFR靶向剂体内的治疗性抗性。 总的来说，这些研究将提供一个理由，将SHAI纳入治疗方案以阻止HGF- 依赖性肿瘤进展，预防或克服HGF依赖于靶向治疗的抗性， 显着改善结肠癌患者的结果。