Development of cancer therapeutic TBK1/IKKi dual inhibitors

癌症治疗TBK1/IKi双重抑制剂的开发

• 批准号: 9893827
• 负责人: Jun-Li Luo
• 金额: $ 43.92万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9893827
• 关键词: Adenocarcinoma; Apoptotic; Binding; Biochemical; Biological; Biological Assay; Biology; Cancer Cell Growth; Carcinoma; Cell Proliferation; Cell Survival; Cells; Chemicals; Critical Pathways; Development; Drug Design; Exhibits; FDA approved; Genetic; Goals; Growth; Growth and Development function; Hormones; Human; In Vitro; Individual; Investigational Drugs; Knock-out; Lead; Libraries; Malignant Neoplasms; Malignant neoplasm of prostate; Methods; Microtubules; Minor; Modeling; Molecular; Molecular Weight; Mus; Oncoproteins; Operations Research; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphotransferases; Play; Property; Prostate Cancer therapy; Prostatic Intraepithelial Neoplasias; Refractory; Research; Research Project Grants; Role; Series; Structure; Structure-Activity Relationship; TBK1 gene; Testing; Therapeutic; Time; Toxic effect; Tubulin; United States; advanced prostate cancer; base; cancer cell; cancer survival; castration resistant prostate cancer; chemotherapy; curative treatments; docetaxel; dosage; efficacy study; efficacy testing; hormone refractory prostate cancer; improved; in vivo; inhibitor/antagonist; knock-down; lead optimization; mouse model; novel; novel strategies; novel therapeutics; public health relevance; tumor; tumor growth

 DESCRIPTION (provided by applicant): The goal of the proposed research is to develop potent and selective TBK1/IKKi dual inhibitors for the treatment of castration resistant prostate cancer (CRPC). Prostate cancer (PCa) is a heterogeneous malignancy that progresses from prostatic intraepithelial neoplasia to locally invasive adenocarcinoma to hormone-refractory carcinoma. Curative treatments are not available for hormone-refractory PCa. Recently, many studies suggest that the non-canonical IKKs, TBK1 and IKKi, play important roles in tumor growth and development. In preliminary studies we found that both p-TBK1 and p-IKKi were highly expressed in human advanced PCa and CRPC. We found that individual knockdown of either IKKi or TBK1 had minor effects on cell survival while simultaneous knockdown of both TBK1 and IKKi significantly inhibited cell proliferation. In mouse models, we found that knockout of either IKKi or TBK1 had minor effect on CRPC growth, while knockdown of both TBK1 and IKKi significantly suppressed CRPC development. These results suggest that both TBK1 and IKKi are essential for CRPC survival and development. Inhibiting either one alone is not enough to inhibit cancer cell proliferation due to the overlap and compensatory function between them. Thus, simultaneously targeting both TBK1 and IKKi is necessary for the efficient shutdown of cancer cell growth. Accordingly, we have developed several groups of compounds that exhibited high potency of TBK1/IKKi dual inhibition. Treatment of prostate cancer (and other cancers) cells with these compounds dramatically reduced cell proliferation rate. These TBK1/IKKi dual inhibitors also significantly suppressed the growth and development of CRPC in mouse models. Most importantly, these compounds have drug-like properties including low molecular weight, clean CYPs inhibition, and good microsomal stability. We will (1) investigate the anti-tumor efficacy and selectivity of TBK1/IKKi dual inhibitors, and (2) SAR optimization to obtain novel TBK1/IKKi inhibitors that are suitable for Investigational New Drug (IND)-enabling studies. Our studies will lead to development of novel strategies and highly efficient therapeutics for the treatment of human (prostate) cancer.

 描述（由申请人提供）：拟议研究的目标是开发用于治疗去势抵抗性前列腺癌（CRPC）的有效和选择性TBK 1/IKKi双重抑制剂。 前列腺癌（PCa）是一种异质性恶性肿瘤，从前列腺上皮内瘤变发展为局部浸润性腺癌，再发展为难治性癌。 难治性PCa的治愈性治疗不可用。 近年来，许多研究表明非经典IKKs（TBK 1和IKKi）在肿瘤的生长和发展中起重要作用。 在初步研究中，我们发现p-TBK 1和p-IKKi在人类晚期PCa和CRPC中高度表达。 我们发现单独敲除IKKi或TBK 1对细胞存活的影响很小，而同时敲除TBK 1和IKKi显著抑制细胞增殖。 在小鼠模型中，我们发现敲除IKKi或TBK 1对CRPC生长的影响很小，而敲除TBK 1和IKKi均显著抑制CRPC的发展。 这些结果表明，TBK 1和IKKi对CRPC的生存和发展至关重要。 单独抑制其中任何一种都不足以抑制癌细胞增殖，因为它们之间存在重叠和代偿功能。 因此，同时靶向TBK 1和IKKi对于有效关闭癌细胞生长是必要的。 因此，我们已经开发了几组表现出高效力的TBK 1/IKKi双重抑制的化合物。 用这些化合物治疗前列腺癌（和其他癌症）细胞显著降低了细胞增殖率。 这些TBK 1/IKKi双重抑制剂还显著抑制了小鼠模型中CRPC的生长和发育。 最重要的是，这些化合物具有药物样性质，包括低分子量、干净的CYP抑制和良好的微粒体稳定性。 我们将（1）研究TBK 1/IKKi双重抑制剂的抗肿瘤疗效和选择性，以及（2）SAR优化，以获得适用于试验性新药（IND）使能研究的新型TBK 1/IKKi抑制剂。 我们的研究将导致开发新的策略和高效的治疗人类（前列腺癌）的疗法。