Nuclear receptor RORγ inverse agonists/antagonists display tissue- and gene-context selectivity through distinct activities in altering chromatin accessibility and master regulator SREBP2 occupancy.

ABSTRACT: 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 exp

SUBMITTER: Zou H 

PROVIDER: S-EPMC10158160 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature