Research progresses in glucocorticoid receptor and selective glucocorticoid receptor modulators

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1 Chinese Bulletin of Life Sciences Vol. 20, No. 5 Oct., (2008) (glucocorticoids, GCs) (glucocorticoid receptor, GR) GR GR GR Q571; R979 1 A Research progresses in glucocorticoid receptor and selective glucocorticoid receptor modulators LI Qun-yi, YAN Jian-hua, WANG Ming-wei* (The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai , China) Abstract: Glucocorticoids (GCs) are widely used as anti-inflammatory therapeutics. Their physiological and pharmacological actions are mainly mediated by glucocorticoid receptor (GR). As a member of the nuclear receptor superfamily, GR is a ligand-activated transcriptional factor and plays important roles in many physiological and pathological processes. With in-depth knowledge on the molecular mechanisms involved in GRrelated signal transduction pathways, discovery of novel GR modulators has become one of the focal points in drug development, aiming at increasing efficacies and reducing side effects. In this review, we briefly describe the current understanding of molecular structure, biological functions and selective modulators of GR. Key words: glucocorticoids; receptor; modulators 1 (glucocorticoids, GCs) 20 50, (2004CB518902) * wangmw@mail.shcnc.ac.cn

2 801 Altana (Ciclesonide) (<1%) [1] () Metselaar [2] (PEG) PEG (NO) NCX-1015( ) NCX-1022( ) [3,4] (selective glucocorticoid receptor modulators, SGRMs) (glucocorticoid receptor, GR) (heat shock protein, HSP) - GR - -κb (NF-κB) -1(AP-1) GR / (glucocorticoid response elements GREs) Reichardt [5] GR (GR dim/dim ) GR GRE AP-1 GR dim/dim [6] (SGRMs) SGRMs GR NF-κB AP-1 SGRMs 2 GR GR(hGR) 5 (5q31-32) 9 [7] 2 8 hgr mrna 9 hgr mrna (hgrα hgrβ) hgrα 777 hgr hgrβ 742 hgrα [8] (hgrγ) hgrα hgrγ DNA [9] hgrα 3 ( 1) N -1 (AF-1) DNA (DNA binding domain, DBD) (zinc fingers) C (1igand binding domain, LBD) -2(AF-2) AP-1 NF-κB [10]

3 802 1 α (hgrα) DBD DNA Hinge LBD Zinc fingers Dimerization GRα HSP90 HSP70 HSP40 P23 (immunophilin) GRα GRα HSP hgrα GRα GRE - [11] 3 GRα GRα / GRE GRE 15 AGAACAnnnTGTTCT(n ) [12] GRα / GRE GRα-DNA [13] GRα GRα DNA GRα GRα [14] Cre/ loxp GRα 458 (GR dim/dim ) (TAT) (PEPCK) [5] (PEPCK) (TAT) (serine dehydrogenase) [15] (GS) [16] -1(lipocortin- 1) (secretory leukocyte protease inhibitor SLPI) IL-10 [17] 4 GRα GRα GRE(negative GRE ngre) (pro-opiomelanocortin POMC) (osteocalcin) / 4(withno-lysine (K) kinase-4, WNK4) GRE GRα [18-20] GRα - ( NF-κB AP-1) GRα NF-κB NF-κB Rel p65/p50 NF-κB NF-κB IκB IL-1 TNF-α LPS IκB IκB 26S NF-κB NF-κB IL-1β TNF-α (GM-CSF) COX-2 inos [21] GRα NF-κB p65 NF-κB NF-κB GRα GRα NF-κB McKay Cidlowski [22] GRα p65 - NF-κB

4 803 NF-κB hgrα NF-κB CBP SRC-1 [23] CBP GRα NF-κB NF-κB GRα SRC-1 NF-κB GRα [24] GRα 2(histone deacytelase 2, HDAC2) p65 DNA [25] HDAC2 GRα GRα IκB IκB IκB NF-κB NF-κB [26] 1(mitogen- and stress-activated protein kinase 1, MSK1) NF-κB p65 S276 H3 S10 IL-6 Beck [27] GR MSK1 CRM1 MSK1 MSK1 p65 H3 NF-κB Lu [28] GR RhoB HO-8910 RhoB GR NF-κB 4.2 GRα AP-1 AP-1 AP-1 Jun (c-jun v-jun Jun-B Jun-D) Fos (c- Fos Fos-B Fra-l Fra-2) c-fos-c-jun AP-1 Jun N- (JNK) c-jun Jun Fos AP-1 [29] NF-κB GRα c-jun - GRα GRα (LBD) JNK MKK7-JNK MKK7 JNK c-jun JNK AP-1 [30] Olivier [31] GR 6 (TRIP6) GRα TRIP6 (nuclear TRIP6, ntrip6) AP-1 NF-κB GRα ntrip6 ntrip6 AP-1 NF-κB 4.3 GRα p38 MAPK COX-2 TNF-α IL-6 IL-8 mrna Toll 2 (TLR2) MAPK 1(MAPK phosphatase 1, MKP-1) JNK ERK p38 ( ) COX-2 mrna TLR2 [32-34] NF-κB AP-1 GRα GRα T (nuclear factor of activated T cells NF-AT) NF-AT DNA IL-4 [35] 3(interferon regulatory factor 3, IRF3) Toll 4(TLR 4) ATF p300/cbp IFN-α/β (interferon stimulated genes, ISGs) Reily [36] 1(glucocorticoid receptor-interacting protein 1, GRIP1) IRF3 IRF3 GRα IRF3 GRIP1 IRF3 5 GR GR GR / ( 2) RU24858

5 804 RU24858 GR AP-1 THP-1 RU24858 LPS IL-1β RU24858 [37] RU24858 [38] RU24858 RU24858 ZK AL-438 AL-438 GR E-selectin IL-6 TAT AL-438 AL-438 [39] ZK THP-1 (peripheral blood mononuclear cell PBMC) IL-8 IL-12 p70 TNF-α H4-II-E-C3 (TAT) ZK ZK / [40] Compound 25 GR (IC nmol/l) IL-6 (TAT) (GS) LPS TNF-α Compound 25 TNF-α (ED 50 4 mg/kg) [41] Compound A GR GR GRE (ChIP) Compound A GR GRE Compound A TNF-α IL-6 Compound A NF-κB 2

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