XY-018

The nuclear receptor RORγ is a major driver of autoimmune diseases and certain types of cancer due to its aberrant function in T helper 17 (Th17) cell differentiation and tumor cholesterol metabolism, respectively. Compound screening using the classic receptor-coactivator interaction perturbation scheme led to identification of many small-molecule modulators of RORγ(t). We report here that inverse agonists/antagonists of RORγ such as VTP-43742 derivative VTP-23 and TAK828F, which can potently inhibit the inflammatory gene program in Th17 cells, unexpectedly lack high potency in inhibiting the growth of TNBC tumor cells. In contrast, antagonists such as XY018 and GSK805 that strongly suppress tumor cell growth and survival display only modest activities in reducing Th17-related cytokine expression. Unexpectedly, we found that VTP-23 significantly induces the cholesterol biosynthesis program in TNBC cells. Our further mechanistic analyses revealed that VTP-23 enhances the local chromatin accessibility, H3K27ac mark and the cholesterol master regulator SREBP2 recruitment at the RORγ binding sites, whereas XY018 exerts the opposite activities. Yet, they display similar inhibitory effects on circadian rhythm program. Similar distinctions and contrasting activities between TAK828F and SR2211 in their effects on local chromatin structure at Il17 genes were also observed. Together, our study shows for the first-time that structurally distinct RORγ antagonists possess different or even contrasting activities in tissue/cell-specific manner. Our findings also highlight that the activities at natural chromatin are key determinants of RORγ modulators' tissue selectivity.

Prostate cancer (PCa) is a malignant tumor with an extremely high prevalence. Doxorubicin is the first‐line clinical treatment for castration‐resistant PCa. Clinically, relapse is almost inevitable due to the cancer cells' increasing resistance to doxorubicin. Our previous studies have revealed that retinoic acid‐related orphan nuclear receptor γ (RORγ) is a key protein for cancer progression and a promising target for PCa therapy. Though, RORγ's role and mechanism in doxorubicin‐resistant PCa remain unclear. To study the mechanism of doxorubicin resistance, we generated a doxorubicin‐resistant PCa cell line C4‐2B (C4‐2B DoxR) in this study, by culturing cells in an increasing doxorubicin concentration. Here, we show that RORγ expression was upregulated in C4‐2B DoxR cells compared with that in normal C4‐2B cells. The RORγ‐stably‐overexpressing PCa cell line constructed by lentiviral transfection showed an obvious improvement in doxorubicin resistance and a trend toward castration resistance. Furthermore, RORγ‐specific small molecule inhibitors XY018, GSK805, and SR2211 can significantly inhibit the proliferation of C4‐2B DoxR cells and promote their apoptosis. Collectively, these results have demonstrated the correlation between the upregulation of RORγ and the development of PCa's doxorubicin resistance, thus providing new ideas for solving the problem of chemotherapy drug resistance in PCa.