Karki Keshav, Mohankumar Kumaravel, Schoeller Abigail, Martin Gregory, Shrestha Rupesh, Safe Stephen
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77843, USA.
Cancers (Basel). 2021 May 29;13(11):2682. doi: 10.3390/cancers13112682.
Nuclear receptor 4A1 (NR4A1, Nur77, TR3) is more highly expressed in breast and solid tumors compared to non-tumor tissues and is a pro-oncogenic factor in solid tumor-derived cancers. NR4A1 regulates cancer cell growth, survival, migration, and invasion, and bis-indole-derived compounds (CDIMs) that bind NR4A1 act as antagonists and inhibit tumor growth. Preliminary structure-binding studies identified 1,1-bis(3'-indolyl)-1-(3,5-disubstitutedphenyl)methane analogs as NR4A1 ligands with low K values; we further investigated the anticancer activity of the four most active analogs (K's ≤ 3.1 µM) in breast cancer cells and in athymic mouse xenograft models. The treatment of MDA-MB-231 and SKBR3 breast cancer cells with the 3-bromo-5-methoxy, 3-chloro-5-trifluoromethoxy, 3-chloro-5-trifluoromethyl, and 3-bromo-5-trifluoromethoxy phenyl-substituted analogs decreased cell growth and the expression of epidermal of growth factor receptor (EGFR), hepatocyte growth factor receptor (cMET), and PD-L1 as well as inhibited mTOR phosphorylation. In addition, all four compounds inhibited tumor growth in athymic nude mice bearing MDA-MB-231 cells (orthotopic) at a dose of 1 mg/kg/d, which was not accompanied by changes in body weight. These 3,5-disubstituted analogs were the most potent CDIM/NR4A1 ligands reported and are being further developed for clinical applications.
与非肿瘤组织相比，核受体4A1（NR4A1，Nur77，TR3）在乳腺癌和实体瘤中表达更高，是实体瘤衍生癌症中的促癌因子。NR4A1调节癌细胞的生长、存活、迁移和侵袭，与NR4A1结合的双吲哚衍生化合物（CDIMs）作为拮抗剂发挥作用并抑制肿瘤生长。初步的结构结合研究确定1,1-双（3'-吲哚基）-1-（3,5-二取代苯基）甲烷类似物为低K值的NR4A1配体；我们进一步研究了四种活性最高的类似物（K值≤3.1µM）在乳腺癌细胞和无胸腺小鼠异种移植模型中的抗癌活性。用3-溴-5-甲氧基、3-氯-5-三氟甲氧基、3-氯-5-三氟甲基和3-溴-5-三氟甲氧基苯基取代的类似物处理MDA-MB-231和SKBR3乳腺癌细胞，可降低细胞生长以及表皮生长因子受体（EGFR）、肝细胞生长因子受体（cMET）和PD-L1的表达，并抑制mTOR磷酸化。此外，所有四种化合物均以1mg/kg/d的剂量抑制携带MDA-MB-231细胞（原位）的无胸腺裸鼠的肿瘤生长，且体重无变化。这些3,5-二取代类似物是报道的最有效的CDIM/NR4A1配体，正在进一步开发用于临床应用。
