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

SGK1 激酶抑制剂的开发，SGK1 激酶是甲状腺未分化癌的关键靶点

• 批准号: 10330047
• 负责人: Jim Zapf
• 金额: $ 8.63万
• 依托单位: VISIONARY PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10330047
• 关键词: AKT inhibition; AKT1 gene; Active Sites; Address; Administrative Supplement; Animal Model; Apoptotic; BRAF gene; Biological; Biological Assay; Biological Markers; Budgets; Cancer Model; Cancer Patient; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemicals; Chemoresistance; Clinical Trials; Complication; Development; Dose; Epigenetic Process; Event; Face; Formulation; Funding; Future; Genetic; Goals; Growth; Guidelines; Human Cell Line; In Vitro; Laboratories; Lead; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Measures; Medical; Medicine; Metabolic; Molecular; Mus; Mutation; Nature; Neoplasm Metastasis; Outcome; PI3K/AKT; Paclitaxel; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Phase; Phosphotransferases; Prognosis; Property; Proto-Oncogene Proteins c-akt; Resistance; Safety; Sgk protein; Small Business Innovation Research Grant; Study models; Testing; Treatment Efficacy; United States; Variant; Woman; Work; Xenograft Model; Xenograft procedure; anaplastic thyroid cancer; anticancer research; cancer cell; college; cost; effective therapy; efficacy study; enantiomer; human model; in vivo; in vivo Model; inhibitor/antagonist; lead candidate; lead series; method development; neoplastic cell; new therapeutic target; novel; pharmacokinetics and pharmacodynamics; phase 1 study; preclinical development; response; standard of care; targeted agent; targeted treatment; thyroid neoplasm; tumor

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.

摘要 本管理补充文件适用于目标2-1：合成足够量的化合物以支持异种移植 问题研究我们的目标仍然与我们最初的建议相同。出乎意料的是，我们发现， 与非手性化合物相比，手性中心赋予我们的先导化合物一个很好的轮廓。我们发现手性先导化合物 对SGK 1的选择性高于AKT 1（20倍），在细胞中具有活性（<100 nM -比其他SGK 1高20倍 抑制剂），具有良好的ADME和PK，并且没有公认的安全性问题。FDA指南要求任何IND药物 是手性纯的目前，我们的手性先导化合物的材料、劳动力和纯化是 比它们的非手性表亲贵得多。在未来，这些成本可能会降低， 化学方法开发研究，但此类研究超出了我们的建议范围。因此，在本发明的一个方面， 我们的原始预算不足以制备用于功效研究的化合物（目标2-1）。 甲状腺癌是美国增长最快的癌症，现在是第五大流行病 女性的癌症虽然大多数甲状腺癌是可以治愈的，但一个子集（在美国约2-5%，在美国高达20%）是可以治愈的。 全世界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， 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，PI 3 K/AKT通路的激活是甲状腺肿瘤进展的关键事件。 低级别至侵袭性亚型，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，PI 3 K效应血清和糖皮质激素- 调节激酶1（SGK 1）深刻影响甲状腺癌细胞的增殖和生存，尽管完整的PI 3 K AKT活性。这表明SGK 1是PI 3 K转化机制的一个不可或缺的组成部分 因此代表了ATC的新的治疗靶点。在第一阶段，我们根据历史经验优化了销售线索 困难的目标。鉴定的手性先导化合物具有特殊的抗增殖和pNDRG 1生物标志物活性 (73 nM，Cpd 613），比其他已知的SGK 1抑制剂有效20倍。行政 补充剂将使我们能够生产手性化合物，需要在体内显示概念验证功效。 ATC模型一旦制成，我们最好的铅将在阿尔伯特爱因斯坦学院的ATC异种移植模型中进行测试 我们的合作者Antonio Di Cristofano博士是甲状腺领域公认的领导者， 癌症研究 成功完成I期SBIR里程碑将证明体内优化和临床前研究是合理的。 在II期SBIR研究中开发先导系列，目的是治疗ATC和低分化 甲状腺癌（PDTC）是一种甲状腺癌变体，与ATC有许多共同特征。最后，安全， 药理学和毒理学特征将用于II期研究，以选择IND启动研究的候选药物。