Development of inhibitors of the SGK1 kinase, a critical target in anaplastic thyroid cancer

摘要 本行政副刊用于目标2-1：合成足够数量的化合物以支持异种移植 学习。我们的目标仍然在我们最初提议的范围内。出乎意料的是，我们发现添加一个 手性中心提供了一个关于我们的先导化合物与非手性化合物的很好的轮廓。我们证明了手性导联 对SGK1比AKT1有选择性(20倍)，在细胞中活性(&lt；100 NM-20倍于其他SGK1 抑制剂)，有良好的ADME和PK，没有公认的安全问题。FDA指南要求任何IND药物 从我们的线索中衍生出手性纯净。目前，我们手性引线的材料、人工和提纯是 比它们的非手性表亲贵得多。未来，这些成本可能会通过以下方式降低 化学方法发展研究，但这类研究不在我们提议的范围之内。因此， 我们最初的预算不足以为功效研究(目标2-1)准备化合物。 甲状腺癌是美国增长最快的癌症，现在是第五大最常见的癌症 女性患癌症。尽管大多数甲状腺癌是可以治愈的，但有一部分(在美国约为2%-5%，在美国高达 全球15%)总是致命的。由于这些侵袭性甲状腺癌缺乏有效的治疗方法，他们 占甲状腺癌死亡总数的40%-50%。遗传学、免疫组织化学、表观遗传学和动物 模型研究表明，PI3K/AKT通路的激活是甲状腺肿瘤从 低级别到侵袭性亚型，如间变性甲状腺癌(ATC)。我们最近提供了 令人信服的体外和体内证据表明，PI3K效应血清和糖皮质激素的丢失或抑制- 尽管PI3K完整，但受调控的蛋白1(SGK1)对甲状腺癌细胞的增殖和存活有深远影响 和AKT活性。这表明SGK1是PI3K转化机制不可或缺的组成部分 从而为ATC提供了一个新的治疗靶点。在第一阶段，我们从历史上优化了这方面的销售线索 难对付的目标。已鉴定的手性先导化合物具有特殊的抗增殖活性和pNDRG1生物标志物活性 (73 nm，CPD 613)，这个数值是其他已知SGK1抑制剂的20倍。A管理人员 补充剂将使我们能够生产出需要在体内显示概念验证功效的手性化合物 ATC的模型。一旦取得成功，我们最好的领先优势将在阿尔伯特·爱因斯坦学院的ATC异种移植模型上进行测试 在我们的合作者安东尼奥·迪·克里斯托瓦诺博士的实验室里，他是公认的甲状腺领域的领导者 癌症研究 第一阶段SBIR里程碑的成功完成将证明体内优化和临床前 以治疗ATC和低分化为目标的第二阶段SBIR研究中的先导系列研究进展 甲状腺癌(PDTC)，一种与ATC有许多共同特征的甲状腺癌变体。最后，安全， 在第二阶段将使用药理学和毒理学概况来选择IND使能研究的候选人。

ABSTRACT This Administrative Supplement is for Aim 2-1: Synthesize sufficient compound quantities to support xenograft studies. Our aims remain within the same scope of our original proposal. Unexpectedly, we found that adding a chiral center confers a great profile on our leads versus non chiral compounds. We showed that chiral leads are selective for SGK1 versus AKT1 (20-fold), active in cells (<100 nM – 20-fold better than other SGK1 inhibitors), have good ADME & PK and no recognized safety issues. FDA guidelines require any IND drug derived from our leads to be chirally pure. At present, materials, labor, and purification of our chiral leads is substantially more expensive than of their nonchiral cousins. In the future, these costs may be reduced via chemical methods development studies, however such studies are beyond the scope of our proposal. As such, our original budget is insufficient to prepare compound for efficacy studies (Aim 2-1). Thyroid cancer is the most rapidly increasing cancer in the United States and it is now the fifth most prevalent cancer in women. Although most thyroid cancers are curable, a subset (~2-5% in the United States and up to 15% worldwide) is invariably fatal. Because these aggressive thyroid cancers lack effective therapies, they account for 40-50% of total thyroid cancer deaths. Genetic, immunohistochemical, epigenetic and animal model studies show that activation of the PI3K/AKT pathway is a pivotal event as thyroid tumors progress from low grade to aggressive subtypes such as anaplastic thyroid cancer (ATC). We have recently provided compelling in vitro and in vivo evidence that the loss or inhibition of the PI3K effector serum and glucocorticoid- regulated kinase 1 (SGK1) profoundly impacts thyroid cancer cell proliferation and survival, despite intact PI3K and AKT activity. This indicates that SGK1 is an integral and essential part of the PI3K transforming machinery and thus represents a novel therapeutic target for ATC. In Phase I, we optimized leads for this historically difficult target. The chiral leads identified have exceptional antiproliferative and pNDRG1 biomarker activities (73 nM, Cpd 613), a value 20-fold more potent than other known SGK1 inhibitors. An Administrative Supplement will allow us to produce chiral compounds need to show proof-of-concept efficacy in an in vivo model of ATC. Once made, our best lead will be tested in a xenograft model of ATC at Albert Einstein College of Medicine in the laboratory of our collaborator, Dr. Antonio Di Cristofano, a recognized leader in thyroid cancer research Successful completion of the Phase I SBIR milestones will justify in vivo optimization and preclinical development of the lead series in Phase II SBIR studies with the goal of treating ATC and poorly differentiated thyroid cancer (PDTC), a thyroid cancer variant that shares many features with ATC. Finally, safety, pharmacology and toxicology profiles will be used in Phase II to select a candidate for IND-enabling studies.