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SUBSTITUTED BENZYLOXYTRICYCLIC COMPOUNDS AS RETINOIC ACID-RELATED ORPHAN RECEPTOR GAMMA T AGONISTS
Structural highlights
DiseaseNCOA1_HUMAN Note=A chromosomal aberration involving NCOA1 is a cause of rhabdomyosarcoma. Translocation t(2;2)(q35;p23) with PAX3 generates the NCOA1-PAX3 oncogene consisting of the N-terminus part of PAX3 and the C-terminus part of NCOA1. The fusion protein acts as a transcriptional activator. Rhabdomyosarcoma is the most common soft tissue carcinoma in childhood, representing 5-8% of all malignancies in children. FunctionRORG_HUMAN Possible nuclear receptor for hydroxycholesterols, the binding of which strongly promotes coactivators recruitment. Essential for thymopoiesis and the development of several secondary lymphoid tissues, including lymph nodes. Involved in lineage specification of uncommitted CD4(+) T-helper cells into Th17 cells. Regulate the expression of several components of the circadian clock.NCOA1_HUMAN Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion. Involved in the coactivation of different nuclear receptors, such as for steroids (PGR, GR and ER), retinoids (RXRs), thyroid hormone (TRs) and prostanoids (PPARs). Also involved in coactivation mediated by STAT3, STAT5A, STAT5B and STAT6 transcription factors. Displays histone acetyltransferase activity toward H3 and H4; the relevance of such activity remains however unclear. Plays a central role in creating multisubunit coactivator complexes that act via remodeling of chromatin, and possibly acts by participating in both chromatin remodeling and recruitment of general transcription factors. Required with NCOA2 to control energy balance between white and brown adipose tissues. Required for mediating steroid hormone response. Isoform 2 has a higher thyroid hormone-dependent transactivation activity than isoform 1 and isoform 3.[1] [2] [3] [4] [5] [6] [7] Publication Abstract from PubMedSubstituted benzyloxy aryl compound 2 was identified as an RORgammat agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated. Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORgammat) agonists.,Harikrishnan LS, Gill P, Kamau MG, Qin LY, Ruan Z, O'Malley D, Huynh T, Stachura S, Cavallaro CL, Lu Z, J-W Duan J, Weigelt CA, Sack JS, Ruzanov M, Khan J, Gururajan M, Wong JJ, Huang Y, Yarde M, Li Z, Chen C, Sun H, Borowski V, Murtaza A, Fink BE Bioorg Med Chem Lett. 2020 Jun 15;30(12):127204. doi: 10.1016/j.bmcl.2020.127204., Epub 2020 Apr 20. PMID:32334911[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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