Structure-based anti-cancer drug development

基于结构的抗癌药物开发

• 批准号: 9190363
• 负责人: Xingming Deng
• 金额: $ 37.05万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-07 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9190363
• 关键词: Agonist; Animal Cancer Model; Antineoplastic Agents; Apoptosis; Apoptotic; Attenuated; Bax protein; Binding; Biological; Cancer Patient; Cell Death; Cisplatin; DNA Sequence Alteration; Databases; Development; Docking; Epidermal Growth Factor Receptor; Failure; Family member; Genetic Engineering; Genetic Models; Human; In Vitro; Induction of Apoptosis; KRAS2 gene; Lead; Link; MAPK3 gene; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mitochondria; Molecular Conformation; Mutation; Names; National Cancer Institute; New Agents; Non-Small-Cell Lung Carcinoma; Outcome; PDPK1 gene; PI3K/AKT; PTEN gene; Pathway interactions; Patients; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Prognostic Marker; Protein Dephosphorylation; Proto-Oncogene Proteins c-akt; Public Health; Radiation; Radiation therapy; Radio; Radioresistance; Ras/Raf; Reporting; Resistance; Role; Serine; Signal Pathway; Signal Transduction; Sirolimus; Site; Structure; Testing; Tumor Tissue; Xenograft procedure; base; cancer cell; cancer therapy; cancer type; cell killing; chemotherapeutic agent; chemotherapy; computerized; cytochrome c; drug development; mTOR Inhibitor; mTOR inhibition; member; mitochondrial membrane; mutant; novel; outcome forecast; predictive marker; programs; public health relevance; radioresistant; screening; small molecule; survival outcome; targeted agent; tetrahydrobiopterin; therapeutic target; therapy resistant

 DESCRIPTION (provided by applicant): Survival outcomes remain poor for lung cancer patients, in part due to genetic alterations-mediated survival signaling pathways in lung cancer cells and treatment resistance. Bax functions as an essential gateway to apoptotic cell death. We previously discovered that the serine (S)184 phosphorylation site of Bax is a critical switch to functionally control Bax's proapoptotic activity. AKT and PKC have been identified as physiologic Bax kinases that can directly phosphorylate Bax at S184 site leading to inactivation of its proapoptotic function. It is known that genetic mutations in K-Ras, EGFR and PTEN can activate PI3K/AKT survival pathway leading to increased resistance to radiotherapy or chemotherapy in various cancers, including lung cancer. Increased levels of phospho-Bax (i.e. pBax) were observed in tumor tissues in patients with non-small cell lung cancer (NSCLC). We hypothesize that pBax may provide a new predictive and prognostic biomarker in NSCLC. Expression of constitutively active K-Ras G12D mutant or treatment with radiation, cisplatin or rapamycin resulted in activation of AKT and/or PKC leading to increased phosphorylation of Bax, which may contribute to radio-, chemo- or rapalog resistance. Since increased levels of pBax (i.e. inactive form of Bax) were also observed in both radioresistant and rapalog resistant lung cancer cells as well as K-Ras mutant lung cancer, development of novel small molecules that activate Bax should be critical for treatment of K-Ras mutant lung cancer or overcoming radio- or rapalog resistance. We have identified three small molecule Bax activators (SMBA1-3) that selectively bind the S184 pocket of Bax protein but do not bind other Bcl2 family members. The lead compound SMBA1 not only reverses radioresistance but also overcomes rapalog resistance in vitro. SMBA1 potently represses lung cancer xenografts through induction of apoptosis by activating Bax in tumor tissues. In this proposal, two specific aims have been identified: (1) To determine whether and how genetic alterations or mTOR inhibition regulate Bax phosphorylation leading to Bax inactivation and treatment resistance in human lung cancer cells. Studies will determine whether pBax is a novel prognostic biomarker or therapeutic target in NSCLC patients; (2) Development of novel small molecule Bax activators (SMBA) by targeting the structural pocket around the Bax phosphorylation site for lung cancer therapy. Studies will test the antitumor efficacy of SMBA or in combination with mTOR inhibitor RAD001 or Bcl2 BH4 antagonist BDA-366 in patient-derived xenograft (PDX), radioresistant lung cancer and genetically engineered K-Ras-driven lung cancer animal models. It is expected that a new class of anti-cancer agents and optimal strategies for lung cancer treatment will be developed by targeting Bax.

 描述（由申请方提供）：肺癌患者的生存结局仍然很差，部分原因是肺癌细胞中遗传变异介导的生存信号通路和治疗耐药性。Bax作为凋亡性细胞死亡的重要途径发挥作用。我们先前发现Bax的丝氨酸（S）184磷酸化位点是功能上控制Bax促凋亡活性的关键开关。AKT和PKC β是生理性Bax激酶，可直接磷酸化Bax的S184位点，导致其促凋亡功能失活。已知K-Ras、EGFR和PTEN中的基因突变可以激活PI3K/AKT存活途径，导致包括肺癌在内的各种癌症对放疗或化疗的抗性增加。在非小细胞肺癌（NSCLC）患者的肿瘤组织中观察到磷酸化Bax（即pBax）水平升高。我们假设pBax可能为NSCLC提供一种新的预测和预后生物标志物。组成型活性K-Ras G12D突变体的表达或用辐射、顺铂或雷帕霉素处理导致AKT和/或PKC β的活化，导致Bax的磷酸化增加，这可能有助于放射性、化学或雷帕霉素抗性。由于在放射抗性和雷帕霉素抗性肺癌细胞以及K-Ras突变型肺癌中也观察到pBax（即Bax的无活性形式）水平增加，因此开发激活Bax的新型小分子对于治疗K-Ras突变型肺癌或克服放射性或雷帕霉素抗性应该是至关重要的。我们已经鉴定出三种小分子Bax激活剂（SBA 1 - 3），它们选择性结合Bax蛋白的S184口袋，但不结合其他Bcl2家族成员。先导化合物SMBA1不仅逆转了辐射抗性，而且在体外克服了辐射抗性。SMBA1通过激活肿瘤组织中的Bax诱导细胞凋亡而有效抑制肺癌异种移植物。在该提议中，已经确定了两个具体目标：（1）确定基因改变或mTOR抑制是否以及如何调节Bax磷酸化，从而导致人肺癌细胞中Bax失活和治疗抗性。研究将确定pBax是否是NSCLC患者的新型预后生物标志物或治疗靶点;（2）通过靶向Bax磷酸化位点周围的结构口袋开发新型小分子Bax激活剂（SMBA）用于肺癌治疗。研究将测试SMBA或与mTOR抑制剂RAD001或Bcl 2 BH4拮抗剂BDA-366组合在患者来源的异种移植物（PDX）、放射抗性肺癌和基因工程K-Ras驱动的肺癌动物模型中的抗肿瘤功效。因此，以Bax为靶点有望开发出一类新的抗肿瘤药物和肺癌治疗的最佳策略。