Development of cancer therapeutic TBK1/IKKi dual inhibitors

 描述(申请人提供)：拟议研究的目标是开发有效和选择性的TBK1/IKKI双重抑制剂，用于治疗去势抵抗前列腺癌(CRPC)。前列腺癌(Pca)是一种从前列腺上皮内瘤变到局部浸润性腺癌再到激素非依赖性癌的异质性恶性肿瘤。激素抵抗型前列腺癌目前尚无根治方法。近年来，许多研究表明，非典型的IKKs，即TBK1和IKKI，在肿瘤的生长和发展中起着重要的作用。在前期研究中，我们发现p-Tbk1和p-Ikki在晚期PCa和CRPC中高表达。我们发现，单独敲除Ikki或TBK1对细胞存活的影响很小，而同时敲除TBK1和Ikki则显著抑制细胞增殖。在小鼠模型中，我们发现Ikki或TBK1的敲除对CRPC的生长影响很小，而TBK1和Ikki的敲除都显著抑制了CRPC的发育。这些结果表明，Tbk1和Ikki对CRPC的生存和发育都是必需的。单独抑制其中任何一种都不足以抑制癌细胞的增殖，因为它们之间存在重叠和补偿功能。因此，同时靶向Tbk1和Ikki对于有效地阻止癌细胞生长是必要的。因此，我们开发了几组显示出高效力的TBK1/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)细胞时，细胞增殖率显著降低。这些Tbk1/Ikki双抑制物对小鼠CRPC的生长发育也有明显的抑制作用。最重要的是，这些化合物具有类似药物的性质，包括低分子量，干净的细胞色素P450抑制，以及良好的微粒体稳定性。我们将(1)研究TBK1/IKKI双重抑制剂的抗肿瘤效果和选择性，以及(2)进行SAR优化，以获得适合于研究性新药(IND)使能研究的新型TBK1/IKKI抑制剂。我们的研究将导致开发治疗人类(前列腺癌)的新策略和高效疗法。

 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.