5hjs | pdb_00005hjs
Identification of LXRbeta selective agonists for the treatment of Alzheimer's Disease
Structural highlights
Disease[NCOA1_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. Function[NR1H3_HUMAN] Orphan receptor. Interaction with RXR shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES. LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides. Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (By similarity). [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 PubMedHerein, we describe the development of a functionally selective liver X receptor beta (LXRbeta) agonist series optimized for Emax selectivity, solubility, and physical properties to allow efficacy and safety studies in vivo. Compound 9 showed central pharmacodynamic effects in rodent models, evidenced by statistically significant increases in apolipoprotein E (apoE) and ATP-binding cassette transporter levels in the brain, along with a greatly improved peripheral lipid safety profile when compared to those of full dual agonists. These findings were replicated by subchronic dosing studies in non-human primates, where cerebrospinal fluid levels of apoE and amyloid-beta peptides were increased concomitantly with an improved peripheral lipid profile relative to that of nonselective compounds. These results suggest that optimization of LXR agonists for Emax selectivity may have the potential to circumvent the adverse lipid-related effects of hepatic LXR activity. Identification and in Vivo Evaluation of Liver X Receptor beta-Selective Agonists for the Potential Treatment of Alzheimer's Disease.,Stachel SJ, Zerbinatti C, Rudd MT, Cosden M, Suon S, Nanda KK, Wessner K, DiMuzio J, Maxwell J, Wu Z, Uslaner JM, Michener MS, Szczerba P, Brnardic E, Rada V, Kim Y, Meissner R, Wuelfing P, Yuan Y, Ballard J, Holahan M, Klein DJ, Lu J, Fradera X, Parthasarathy G, Uebele VN, Chen Z, Li Y, Li J, Cooke AJ, Bennett DJ, Bilodeau MT, Renger J J Med Chem. 2016 Apr 14;59(7):3489-98. doi: 10.1021/acs.jmedchem.6b00176. Epub, 2016 Apr 1. PMID:27011007[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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