Oral formulation for novel inhibitor of 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。这样的突变 可能导致三种主要RAS蛋白亚型中的一种或多种结构性激活，包括H-RAS，NRAS， 或K-RAS，它们介导了导致细胞生长失控和肿瘤的重要信号通路 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。 在结直肠癌、肺癌和胰腺肿瘤中尤为常见。Ras基因突变也出现在肿瘤中。 对化疗和/或放射有抵抗力的人。目前还没有批准的可用药物 美国食品和药物管理局可以选择性地抑制由活性物质驱动的肿瘤生长 拉斯。利用基于细胞的表型筛选，ADT制药公司发现了一种新的化合物 有效和选择性地抑制含有激活的RAS的肿瘤细胞的系列。在广泛的化学物质 OPTIMIZATION，一种临床前开发候选药物DC070-547被确定为显示低纳摩尔 含有活化RAS的肿瘤细胞生长抑制IC50值，而缺乏活化RAS的肿瘤细胞生长抑制IC50值， 和来自正常组织的细胞，是不敏感的。数据显示，该药物与RAS相互作用，破坏 RAS-Raf相互作用并抑制Raf/MAPK和PI3K/Akt通路的下游信号。 DC070-547在小鼠腹腔注射后的异种移植模型中显示出很强的体内抗肿瘤活性。行政管理 没有明显的毒性和诱人的类药物特性，适合口服给药。在此，我们建议 开发一种口服配方，以实现进一步的临床前开发，并将与Catalent，Inc.密切合作 公司拥有丰富的配方专业知识。目标1将大量和广泛地合成DC070-547 在配方前研究中对化合物的物理化学性质进行表征。Aim 2将在 DC070-547和Aim 3的至少4个独特配方将确定体内药代动力学特征 并将选择最终剂量以评估其在小鼠身上的耐受性。我们预计会有一场临床 将从该项目中产生口服给药最佳配方的开发候选者 高级到第二阶段SBIR应用，包括进一步的临床前开发，以优化剂量和 时间表、GMP放大合成和GLP毒性评估，以支持IND应用于人类 RAS驱动的癌症患者的临床试验。

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.