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（由申请人提供）：肺癌患者的生存结果仍然不佳，部分原因是肺癌细胞中基因改变介导的生存信号通路和治疗耐药性我们之前发现。 Bax 的丝氨酸 (S)184 磷酸化位点是功能性控制 Bax 促凋亡活性的关键开关，并且 PKC 已被确定为生理性 Bax 激酶。可以直接在 S184 位点磷酸化 Bax，导致其促凋亡功能失活。众所周知，K-Ras、EGFR 和 PTEN 的基因突变可以激活 PI3K/AKT 生存途径，导致各种癌症对放疗或化疗的耐药性增加。在非小细胞肺癌 (NSCLC) 患者的肿瘤组织中观察到磷酸-Bax（即 pBax）水平升高。 pBax 可能为 NSCLC 提供新的预测和预后生物标志物。组成型活性 K-Ras G12D 突变体的表达或放射、顺铂或雷帕霉素治疗导致 AKT 和/或 PKC 激活，从而导致 Bax 磷酸化增加。由于在放射抗性和抗性中也观察到了 pBax（即 Bax 的非活性形式）水平的增加。 rapalog 耐药性肺癌细胞以及 K-Ras 突变型肺癌细胞，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或 rapalog 耐药性至关重要 我们已经鉴定了三种小分子 Bax。选择性结合 Bax 蛋白的 S184 口袋但不结合其他 Bcl2 家族成员的激活剂 (SMBA1-3)。先导化合物 SMBA1 不仅可以逆转放射抗性，还可以克服 rapalog。 SMBA1 通过激活肿瘤组织中的 Bax 诱导细胞凋亡来有效抑制肺癌异种移植物。在该提案中，已经确定了两个具体目标：（1）确定改变遗传或 mTOR 抑制是否以及如何调节 Bax 磷酸化。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标；（2）开发新型小分子 Bax 激活剂。 (SMBA) 通过靶向 Bax 磷酸化位点周围的结构袋进行肺癌治疗 研究将测试 SMBA 或与 mTOR 抑制剂 RAD001 或 Bcl2 BH4 拮抗剂 BDA-366 联合使用在患者来源的异种移植物 (PDX) 中的抗肿瘤功效，抗辐射。肺癌和基因工程K-Ras驱动的肺癌动物模型预计将通过靶向开发一类新型抗癌药物和肺癌治疗的最佳策略。巴克斯。