Karaboga Husna, Huang Wentao, Srivastava Shivangi, Widmann Scott, Addanki Sridevi, Gamage Kasuni Thawalama, Mazhar Zahra, Ebalunode Jerry O, Briggs James M, Gustafsson Jan-Åke, Filgueira Carly S, Gilbertson Scott R, Lin Chin-Yo
College of Pharmacy, Guangxi Medical University, Qingxiu District, Nanning, Guangxi, China.
Department of Nanomedicine, Houston Methodist Research Institute, Houston, Texas 77030, United States.
ACS Chem Biol. 2020 Nov 20;15(11):2916-2928. doi: 10.1021/acschembio.0c00546. Epub 2020 Oct 19.
Pancreatic ductal adenocarcinoma (PDAC) is the predominant form of pancreatic cancer. PDACs harbor oncogenic mutations in the gene, and ongoing efforts to directly target its mutant protein product to inhibit tumor growth are a priority not only in pancreatic cancer but in other malignancies such as lung and colorectal cancers where is also commonly mutated. An alternative strategy to directly targeting KRAS is to identify and target druggable receptors involved in dysregulated cancer hallmarks downstream of KRAS dysregulation. Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-modulated transcription factors and are involved in the regulation of genes which function in key cancer-related processes, including cholesterol transport, lipid and glucose metabolism, and inflammatory and immune responses. Modulation of LXRs via small molecule ligands has emerged as a promising approach for directly targeting tumor cells or the stromal and immune cells within the tumor microenvironment. We have previously shown that only one of the two LXR subtypes (LXRβ) is expressed in pancreatic cancer cells, and targeting LXR with available synthetic ligands blocked the proliferation of PDAC cells and tumor formation. In a screen of a focused library of drug-like small molecules predicted to dock in the ligand-binding pocket of LXRβ, we identified two novel LXR ligands with more potent antitumor activity than current LXR agonists used in our published studies. Characterization of the two lead compounds (GAC0001E5 and GAC0003A4) indicates that they function as LXR inverse agonists which inhibit their transcriptional activity. Prolonged treatments with novel ligands further revealed their function as LXR "degraders" which significantly reduced LXR protein levels in all three PDAC cell lines tested. These findings support the utility of these novel inhibitors in basic research on ligand design, allosteric mechanisms, and LXR functions and their potential application as treatments for advanced pancreatic cancer and other recalcitrant malignancies.
胰腺导管腺癌（PDAC）是胰腺癌的主要形式。PDAC在该基因中存在致癌突变，目前直接靶向其突变蛋白产物以抑制肿瘤生长的研究不仅是胰腺癌研究的重点，在其他恶性肿瘤如肺癌和结直肠癌中也是重点，因为在这些肿瘤中该基因也经常发生突变。直接靶向KRAS的另一种策略是识别并靶向参与KRAS失调下游癌症特征失调的可药物化受体。肝脏X受体（LXRs）是配体调节转录因子核受体家族的成员，参与调控在关键癌症相关过程中发挥作用的基因，包括胆固醇转运、脂质和葡萄糖代谢以及炎症和免疫反应。通过小分子配体调节LXRs已成为直接靶向肿瘤细胞或肿瘤微环境中的基质细胞和免疫细胞的一种有前景的方法。我们之前已经表明，两种LXR亚型中只有一种（LXRβ）在胰腺癌细胞中表达，用现有的合成配体靶向LXR可阻断PDAC细胞的增殖和肿瘤形成。在一个预计可对接至LXRβ配体结合口袋的类药物小分子聚焦文库筛选中，我们鉴定出两种新型LXR配体，其抗肿瘤活性比我们已发表研究中使用的现有LXR激动剂更强。对两种先导化合物（GAC0001E5和GAC0003A4）的表征表明，它们作为LXR反向激动剂发挥作用，抑制其转录活性。用新型配体进行长时间处理进一步揭示了它们作为LXR“降解剂”的功能，可显著降低所有三种测试的PDAC细胞系中的LXR蛋白水平。这些发现支持了这些新型抑制剂在配体设计、变构机制和LXR功能的基础研究中的实用性，以及它们作为晚期胰腺癌和其他难治性恶性肿瘤治疗方法的潜在应用。
