Oral formulation for novel inhibitor of Ras driven cancers

Ras 驱动癌症的新型抑制剂的口服制剂

• 批准号: 9409488
• 负责人: Michael R Boyd
• 金额: $ 30万
• 依托单位: ADT PHARMACEUTICALS, LLC
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409488
• 关键词: Address; Affinity; Alpha Cell; Binding; Cancer Model; Cells; Chemicals; Clinic; Clinical Trials; Colonic Neoplasms; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Dose; Drug Formulations; Drug Kinetics; Drug resistance; Evaluation; Excipients; FDA approved; Formulation; Future; Generations; Goals; Growth; Guanosine Triphosphate; HCT116 Cells; HRAS gene; Half-Life; Histologic; Human; Injection of therapeutic agent; Investigation; KRAS2 gene; Lead; Lipids; Lung Neoplasms; MAP Kinase Gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Mediating; Medical; Mus; Mutation; National Cancer Institute; Neoplasm Metastasis; Normal tissue morphology; Oral; Particle Size; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenotype; Plasma; Preclinical Drug Development; Property; Protein Isoforms; Protocols documentation; Qualifying; RAS Family Gene; RAS genes; Radiation; Ras Inhibitor; Ras/Raf; Receptor Protein-Tyrosine Kinases; Resistance; Schedule; Series; Signal Pathway; Signal Transduction; Small Business Innovation Research Grant; Solid; Solubility; Solvents; Stress; Surface; Suspensions; Technology; Testing; Tissues; Toxic effect; Tumor Cell Line; United States Food and Drug Administration; Water; Work; Xenograft Model; analog; base; cell growth; chemotherapy; clinical application; clinical development; drug development; effective therapy; efficacy study; improved; in vivo; intraperitoneal; mouse model; mutant; nanomolar; neoplastic cell; novel; novel therapeutic intervention; oncology; pancreatic neoplasm; pharmacokinetic characteristic; preclinical development; preclinical efficacy; preclinical study; ras Oncogene; ras Proteins; research clinical testing; scale up; screening; small molecule; small molecule inhibitor; stability testing; success; tumor; tumor growth; tumorigenesis; uncontrolled cell growth

Mutations in the ras family of genes were first identified in human cancer over 30 years ago. Such mutations may result in the constitutive activation of one or more of three major Ras protein isoforms, including H-Ras, NRas, or K-Ras, that mediate important signaling pathways leading to uncontrolled cell growth and tumor development. Activating mutations of ras genes occur de novo in approximately one-third of all human cancers and are especially prevalent in colorectal, lung, and pancreatic tumors. Mutations in ras also arise in tumors that become resistant to chemotherapy and/or radiation. Currently there are no available drugs approved by the U.S. Food and Drug Administration that can selectively suppress the growth of tumors driven by activated Ras. Employing a cell-based phenotypic screen, ADT Pharmaceuticals Inc. has discovered a novel compound series that potently and selectively inhibits tumor cells harboring activated Ras. Following extensive chemical optimization, a preclinical development candidate, DC070-547, was identified that shows low nanomolar growth inhibitory IC50 values in tumor cells harboring activated Ras, while tumor cells lacking activated Ras, and cells derived from normal tissues, are insensitive. Data suggest that the drug interacts with Ras to disrupt Ras-Raf interactions and suppress downstream signaling of both the Raf/MAPK and PI3K/Akt pathways. DC070-547 shows strong in vivo antitumor activity in a mouse xenograft model following i.p. administration with no discernible toxicity and attractive drug-like properties feasible for oral delivery. Here we propose to develop an oral formulation to enable further preclinical development and will work closely with Catalent, Inc., a company with extensive formulation expertise. Aim 1 will synthesize DC070-547 in bulk and extensively characterize the physiochemical properties of the compound in pre-formulation studies. Aim 2 will develop at least 4 unique formulations of DC070-547 and Aim 3 will determine the in vivo pharmacokinetic characteristics of the formulations and will select a final dose to be evaluated for tolerability in mice. We anticipate a clinical development candidate in an optimal formulation for oral delivery will emerge from this project that will be advanced to a Phase II SBIR application involving further preclinical development to optimize dose and schedule, GMP scale-up synthesis, and GLP toxicity assessment to support an IND application for human clinical trials in patients with Ras-driven cancers.

ras基因家族的突变在30多年前首次在人类癌症中被发现。此类突变 可导致三种主要Ras蛋白同种型中的一种或多种的组成性激活，包括H-Ras，NRas， 或K-Ras，介导重要的信号通路，导致细胞生长失控和肿瘤 发展ras基因的激活突变发生在大约三分之一的人类癌症中 并且在结肠直肠、肺和胰腺肿瘤中尤其普遍。ras突变也出现在肿瘤中 对化疗和/或放疗有抵抗力。目前，没有药物被批准。 美国食品和药物管理局，可以选择性地抑制肿瘤的生长驱动的激活 拉斯采用基于细胞的表型筛选，ADT Pharmaceuticals Inc.发现了一种新的化合物 一系列有效且选择性地抑制携带活化Ras的肿瘤细胞。在广泛的化学 优化后，临床前开发候选药物DC 070 -547被鉴定为低纳摩尔浓度， 含有活化Ras的肿瘤细胞的生长抑制IC 50值，而缺乏活化Ras的肿瘤细胞， 和来自正常组织的细胞是不敏感的。数据表明，药物与Ras相互作用， Ras-Raf相互作用并抑制Raf/MAPK和PI 3 K/Akt途径的下游信号传导。 DC 070 -547在小鼠异种移植模型中i. p.给药后显示出较强的体内抗肿瘤活性 没有可辨别的毒性和适于口服递送的吸引人的药物样性质。在此，我们建议 开发口服制剂，以实现进一步的临床前开发，并将与Catalent，Inc.密切合作，一 公司拥有丰富的配方专业知识。目的1是大量合成DC 070 -547， 在处方前研究中表征化合物的理化性质。Aim 2将在 DC 070 -547和Aim 3的至少4种独特制剂将确定体内药代动力学特征 并将选择最终剂量以评估小鼠的耐受性。我们预计会出现临床 开发候选人在最佳配方口服将出现从这个项目，将 进入II期SBIR应用，涉及进一步的临床前开发以优化剂量， 时间表、GMP放大合成和GLP毒性评估，以支持人用IND申请 在Ras驱动的癌症患者中进行的临床试验。