Dataset Information

Discovery of Retinoic Acid-Related Orphan Receptor ?t Inverse Agonists via Docking and Negative Image-Based Screening.

ABSTRACT: Retinoic acid-related orphan receptor ?t (ROR?t) has a vital role in the differentiation of T-helper 17 (TH17) cells. Potent and specific ROR?t inverse agonists are sought for treating TH17-related diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. Here, the aim was to discover novel ROR?t ligands using both standard molecular docking and negative image-based screening. Interestingly, both of these in silico techniques put forward mostly the same compounds for experimental testing. In total, 11 of the 34 molecules purchased for testing were verified as ROR?t inverse agonists, thus making the effective hit rate 32%. The pIC50 values for the compounds varied from 4.9 (11 ?M) to 6.2 (590 nM). Importantly, the fact that the verified hits represent four different cores highlights the structural diversity of the ROR?t inverse agonism and the ability of the applied screening methodologies to facilitate much-desired scaffold hopping for drug design.

SUBMITTER: Rauhamaki S

PROVIDER: S-EPMC6044741 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Publications

Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening.

Rauhamäki Sanna S Postila Pekka A PA Lätti Sakari S Niinivehmas Sanna S Multamäki Elina E Liedl Klaus R KR Pentikäinen Olli T OT

ACS omega 20180611 6

Retinoic acid-related orphan receptor γt (RORγt) has a vital role in the differentiation of T-helper 17 (TH17) cells. Potent and specific RORγt inverse agonists are sought for treating TH17-related diseases such as psoriasis, rheumatoid arthritis, and type 1 diabetes. Here, the aim was to discover novel RORγt ligands using both standard molecular docking and negative image-based screening. Interestingly, both of these in silico techniques put forward mostly the same compounds for experimental te ...[more]

PMID: 30023945

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Project description:BackgroundAdenoid cystic carcinoma (ACC) is a lethal malignancy of exocrine glands, characterized by the coexistence within tumor tissues of 2 distinct populations of cancer cells, phenotypically similar to the myoepithelial and ductal lineages of normal salivary epithelia. The developmental relationship linking these 2 cell types, and their differential vulnerability to antitumor treatments, remains unknown.MethodsUsing single-cell RNA sequencing, we identified cell-surface markers (CD49f, KIT) that enabled the differential purification of myoepithelial-like (CD49fhigh/KITneg) and ductal-like (CD49flow/KIT+) cells from patient-derived xenografts (PDXs) of human ACCs. Using prospective xenotransplantation experiments, we compared the tumor-initiating capacity of the 2 cell types and tested whether one could differentiate into the other. Finally, we searched for signaling pathways with differential activation between the 2 cell types and tested their role as lineage-specific therapeutic targets.ResultsMyoepithelial-like cells displayed higher tumorigenicity than ductal-like cells and acted as their progenitors. Myoepithelial-like and ductal-like cells displayed differential expression of genes encoding for suppressors and activators of retinoic acid signaling, respectively. Agonists of retinoic acid receptor (RAR) or retinoid X receptor (RXR) signaling (all-trans retinoic acid, bexarotene) promoted myoepithelial-to-ductal differentiation, whereas suppression of RAR/RXR signaling with a dominant-negative RAR construct abrogated it. Inverse agonists of RAR/RXR signaling (BMS493, AGN193109) displayed selective toxicity against ductal-like cells and in vivo antitumor activity against PDX models of human ACC.ConclusionsIn human ACCs, myoepithelial-like cells act as progenitors of ductal-like cells, and myoepithelial-to-ductal differentiation is promoted by RAR/RXR signaling. Suppression of RAR/RXR signaling is lethal to ductal-like cells and represents a new therapeutic approach against human ACCs.

Dataset Information

Discovery of Retinoic Acid-Related Orphan Receptor ?t Inverse Agonists via Docking and Negative Image-Based Screening.

Publications

Discovery of Retinoic Acid-Related Orphan Receptor γt Inverse Agonists via Docking and Negative Image-Based Screening.

Similar Datasets

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