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First-in-Class Inhibitors of Oncogenic CHD1L With Preclinical Activity Against Colorectal Cancer
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2020-06-04 , DOI: 10.1158/1535-7163.mct-20-0106
Joshua M Abbott 1 , Qiong Zhou 1 , Hector Esquer 1 , Laura Pike 1 , Travis P Broneske 1 , Sébastien Rinaldetti 1 , Adedoyin D Abraham 1 , Dominique A Ramirez 2 , Paul J Lunghofer 2 , Todd M Pitts 3, 4 , Daniel P Regan 2 , Aik Choon Tan 3, 4 , Daniel L Gustafson 2, 4 , Wells A Messersmith 3, 4 , Daniel V LaBarbera 1, 4
Affiliation  

Since the discovery of CHD1L in 2008, it has emerged as an oncogene implicated in the pathology and poor prognosis of a variety of cancers, including gastrointestinal cancers. However, a mechanistic understanding of CHD1L as a driver of colorectal cancer has been limited. Until now, there have been no reported inhibitors of CHD1L, also limiting its development as a molecular target. We sought to characterize the clinicopathologic link between CHD1L and colorectal cancer, determine the mechanism(s) by which CHD1L drives malignant colorectal cancer, and discover the first inhibitors with potential for novel treatments for colorectal cancer. The clinicopathologic characteristics associated with CHD1L expression were evaluated using microarray data from 585 patients with colorectal cancer. Further analysis of microarray data indicated that CHD1L may function through the Wnt/TCF pathway. Thus, we conducted knockdown and overexpression studies with CHD1L to determine its role in Wnt/TCF-driven epithelial-to-mesenchymal transition (EMT). We performed high-throughput screening (HTS) to identify the first CHD1L inhibitors. The mechanism of action, antitumor efficacy, and drug-like properties of lead CHD1L inhibitors were determined using biochemical assays, cell models, tumor organoids, patient-derived tumor organoids, and in vivo pharmacokinetics and pharmacodynamics. Lead CHD1L inhibitors display potent in vitro antitumor activity by reversing TCF-driven EMT. The best lead CHD1L inhibitor possesses drug-like properties in pharmacokinetic/pharmacodynamic mouse models. This work validates CHD1L as a druggable target and establishes a novel therapeutic strategy for the treatment of colorectal cancer.

中文翻译:

具有抗结直肠癌临床前活性的致癌 CHD1L 的一流抑制剂

自 2008 年发现 CHD1L 以来,它已成为与多种癌症(包括胃肠道癌)的病理学和不良预后有关的致癌基因。然而,对 CHD1L 作为结直肠癌驱动因素的机制理解是有限的。到目前为止,还没有报道过 CHD1L 抑制剂,这也限制了其作为分子靶点的发展。我们试图表征 CHD1L 和结直肠癌之间的临床病理联系,确定 CHD1L 驱动恶性结直肠癌的机制,并发现第一个具有治疗结直肠癌新疗法潜力的抑制剂。使用来自 585 名结直肠癌患者的微阵列数据评估与 CHD1L 表达相关的临床病理特征。对微阵列数据的进一步分析表明 CHD1L 可能通过 Wnt/TCF 途径起作用。因此,我们对 CHD1L 进行了敲低和过表达研究,以确定其在 Wnt/TCF 驱动的上皮间质转化 (EMT) 中的作用。我们进行了高通量筛选 (HTS) 以确定第一个 CHD1L 抑制剂。使用生化分析、细胞模型、肿瘤类器官、患者来源的肿瘤类器官以及体内药代动力学和药效学确定了先导 CHD1L 抑制剂的作用机制、抗肿瘤功效和类药物特性。先导 CHD1L 抑制剂通过逆转 TCF 驱动的 EMT 显示出有效的体外抗肿瘤活性。最好的先导 CHD1L 抑制剂在药代动力学/药效学小鼠模型中具有类似药物的特性。
更新日期:2020-06-04
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