5g5w
From Proteopedia
Structure guided design and discovery of Indazole ethers as highly potent, non-steroidal Glucocorticoid receptor modulators
Structural highlights
Disease[GCR_HUMAN] Defects in NR3C1 are a cause of glucocorticoid resistance (GCRES) [MIM:138040]; also known as cortisol resistance. It is a hypertensive, hyperandrogenic disorder characterized by increased serum cortisol concentrations. Inheritance is autosomal dominant.[1] [2] [3] [4] [5] [NCOA2_HUMAN] Note=Chromosomal aberrations involving NCOA2 may be a cause of acute myeloid leukemias. Inversion inv(8)(p11;q13) generates the KAT6A-NCOA2 oncogene, which consists of the N-terminal part of KAT6A and the C-terminal part of NCOA2/TIF2. KAT6A-NCOA2 binds to CREBBP and disrupts its function in transcription activation. Function[GCR_HUMAN] Receptor for glucocorticoids (GC). Has a dual mode of action: as a transcription factor that binds to glucocorticoid response elements (GRE), both for nuclear and mitochondrial DNA, and as a modulator of other transcription factors. Affects inflammatory responses, cellular proliferation and differentiation in target tissues. Could act as a coactivator for STAT5-dependent transcription upon growth hormone (GH) stimulation and could reveal an essential role of hepatic GR in the control of body growth. Involved in chromatin remodeling. Plays a significant role in transactivation.[6] [NCOA2_HUMAN] Transcriptional coactivator for steroid receptors and nuclear receptors. Coactivator of the steroid binding domain (AF-2) but not of the modulating N-terminal domain (AF-1). Required with NCOA1 to control energy balance between white and brown adipose tissues.[7] Publication Abstract from PubMedA structure-based design approach led to the identification of a novel class of indazole ether based, non-steroidal glucocorticoid receptor (GR) modulators. Several examples were identified that displayed cell potency in the picomolar range, inhibiting LPS-induced TNF-alpha release by primary peripheral blood mononuclear cells (PBMCs). Additionally, an improved steroid hormone receptor binding selectivity profile, compared to classical steroidal GR agonists, was demonstrated. The indazole ether core tolerated a broad range of substituents allowing for modulation of the physiochemical parameters. A small sub-set of indazole ethers, with pharmacokinetic properties suitable for oral administration, was investigated in a rat antigen-induced joint inflammation model and demonstrated excellent anti-inflammatory efficacy. Discovery of indazole ethers as novel, potent, non-steroidal glucocorticoid receptor modulators.,Hemmerling M, Edman K, Lepisto M, Eriksson A, Ivanova S, Dahmen J, Rehwinkel H, Berger M, Hendrickx R, Dearman M, Jensen TJ, Wissler L, Hansson T Bioorg Med Chem Lett. 2016 Dec 1;26(23):5741-5748. doi:, 10.1016/j.bmcl.2016.10.052. Epub 2016 Oct 19. PMID:27810243[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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Categories: Berger, M | Dahmen, J | Dearman, M | Edman, K | Eriksson, A | Hansson, T | Hemmerling, M | Hendrickx, R | Ivanova, S | Jellesmark-Jensen, T | Lepisto, M | Rehwinkel, H | Wissler, L | Glucocorticoid receptor | Hormone | Ligand complex | Nuclear hormone receptor | Peptide complex | Signaling protein | Steroid receptor
