NR4A1 Ligands as Potent Inhibitors of Breast Cancer Cell and Tumor Growth

Abstract

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 KD values; we further investigated the anticancer activity of the four most active analogs (KD’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.

β‐Glucan produced by Lentinus edodes suppresses breast cancer progression via the inhibition of macrophage M2 polarization by integrating autophagy and inflammatory signals

“…38 Abnormal expression or function of Nur77 can also lead to various diseases, including breast cancer. 27,39,40 Previous studies have reported that p62 plays a role in inhibiting cell autophagy signals; affects proliferation, differentiation, and apoptotic events; is abnormally expressed as an oncogenic factor in several types of tumors; and inhibits the mTOR signaling pathway to coregulate tumorigenesis. 41,42 TRIM59 promotes breast cancer motility by suppressing p62-selective autophagic degradation of PDCD10, 43 and SH003 suppresses breast cancer growth by accumulating p62 in autolysosomes.…”

“…Qin et al reported that Nur77 promotes cigarette smoke‐induced autophagic cell death by increasing the dissociation of Bcl2 from beclin‐1 38 . Abnormal expression or function of Nur77 can also lead to various diseases, including breast cancer 27,39,40 . Previous studies have reported that p62 plays a role in inhibiting cell autophagy signals; affects proliferation, differentiation, and apoptotic events; is abnormally expressed as an oncogenic factor in several types of tumors; and inhibits the mTOR signaling pathway to coregulate tumorigenesis 41,42 .…”

Bis-Indole Derivatives as Dual Nuclear Receptor 4A1 (NR4A1) and NR4A2 Ligands

“…Results of recent studies showed 1,1-bis(3′-indolyl)-1-(3,5-disubstituted-4-hydroxyphenyl) methane (DIM8-3,5) and 1,1-bis(3′-indolyl)-1-(3,5-disubstituted phenyl) methane (DIM-3,5) compounds were NR4A1 ligands that were potent inhibitors of tumor growth in orthotopic mouse xenograft model [ 34 , 35 ]. The following compounds ( Figure 1 ) were synthesized for this study: DIM8-3,5 compounds: DIM8-3,5-Cl2, DIM8-3,5-Br 2 , DIM8-3,5-(Bu) 2 , DIM8-3,5-(CH3) 2 , DIM8-3,5-(OCH 3 ) 2 , DIM8-3-Cl-5-F, DIM8-3-Br-5-OCH 3 , and DIM8-3-Cl-5-OCH 3 ; and DIM-3,5-compounds: DIM-3,5-Cl 2 , DIM-3,5-Br 2 , DIM-3,5-F 2 , DIM-3,5-(CH 3 ) 2 , DIM-3,5-(OCH 3 ) 2 , DIM-3-Br-5-CF 3 , DIM-3-CF-5-CF 3 , DIM-3-F-5-CF 3 , DIM-3-Cl-5-OCF 3 , DIM-3-Br-5-OCF 3 , DIM-3-Br-5-OCH 3 , and DIM-3-Cl-5-OCF 3 .…”

“…Studies in this laboratory investigated the activities of 1,1-bis(3′-indolyl)methane, a metabolite of the phytochemical indole-3-carbinol as a ligand for the aryl hydrocarbon receptor (AhR) and demonstrated that the addition of a substituted phenyl ring (CDIM) resulted in compounds that bound NR4A1 [ 25 , 32 , 33 ]. Several of these CDIM compounds including 1,1-bis(3′-indolyl)-1-(3,5-disubstituted phenyl) methane (DIM-3,5) analogs inhibited mammary tumor growth in an orthotopic athymic nude mouse model and IC 50 values were <1 mg/kg/day [ 34 ]. The potency of the DIM-3,5 and the corresponding DIM8-3,5 analogs [ 35 ] which also contain a 4-hydroxyl group on the phenyl ring suggested that these compounds may not only act as inverse NR4A1 agonists, but also inhibit or inactivate other pro-oncogenic pathways.…”

Therapeutic potential of NR4A1 in cancer: Focus on metabolism

“…Additionally, CsnB also acts as a candidate to downregulate CD36/FABP4 expression, leading to the inhibition of fatty acid uptake and consequent breast cancer cell proliferation in NR4A1-dependent manner ( 41 ). A class of Bisindole-derived (CDIMs) NR4A1 antagonists, such as 1,1-bis(3’-indolyl)-1-(p-hydroxyphenyl) methane (DIM-C-pPhOH), can decrease the expression of NR4A1 in breast, lung, and liver cancer cells to inhibit tumor growth, EMT and stemness ( 97 , 98 ). Additionally, some natural compounds also act as NR4A1 ligands to exhibit an anti-tumor effect.…”