5nft | pdb_00005nft
Glucocorticoid Receptor in complex with AZD5423
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 class of potent, non-steroidal, selective indazole ether based glucocorticoid receptor modulators (SGRMs) was developed for the inhaled treatment of respiratory diseases. Starting from an orally available compound with demonstrated anti-inflammatory activity in rat, a soft drug strategy was implemented to ensure rapid elimination of drug candidates and minimize systemic GR activation. The first clinical candidate 1b (AZD5423) displayed potent inhibition of lung edema in a rat model of allergic airway inflammation following dry powder inhalation combined with a moderate systemic GR-effect, assessed as thymic involution. Further optimization of inhaled drug properties provided a second, equally potent, candidate 15m (AZD7594) that demonstrated an improved therapeutic ratio over the benchmark inhaled corticosteroid 3 (fluticasone propionate) and prolonged inhibition of lung edema, indicating potential for once-daily treatment. Selective Non-steroidal Glucocorticoid Receptor Modulators for the Inhaled Treatment of Pulmonary Diseases.,Hemmerling M, Nilsson S, Edman K, Eirefelt S, Russell W, Hendrickx R, Johnsson E, Karrman-Mardh C, Berger M, Rehwinkel H, Abrahamsson A, Dahm Eacute N J, Eriksson AR, Gabos B, Henriksson K, Hossain N, Ivanova S, Jansson AH, Jensen TJ, Jerre A, Johansson H, Klingstedt T, Lepisto M, Lindsjo M, Mile I, Nikitidis G, Steele J, Tehler U, Wissler L, Hansson T J Med Chem. 2017 Sep 22. doi: 10.1021/acs.jmedchem.7b01215. PMID:28937774[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
