AGN 195183 is an orally active, selective agonist for the retinoic acid receptor α (RARα)[1-2]. AGN 195183 has high affinity for RARα (Kd=3nM) and is inactive against RARβ/γ. AGN 195183 is used in research related to acute myeloid leukemia, multiple myeloma, and breast cancer[3].
In vitro, AGN 195183 (0-1μM) was used to treat the ER-positive human breast cancer cell line T-47D and the ER-negative human breast cancer cell line SK-BR-3 for 1-8 days. AGN 195183 significantly inhibited cell growth[4]. Treatment of the human promyelocytic leukemia cell line NB-4 with AGN 195183 (100nM) for 96 hours effectively induced neutrophil differentiation; co-treatment of NB-4 cells with AGN 195183 (100nM) and 10nM 1,25-dihydroxyvitamin D3 for 96 hours effectively induced monocyte differentiation[5].
In vivo, AGN 195183 (4mg/kg/day and 20mg/kg/day) was administered orally to treat Wistar rats with glomerulonephritis (Thy-GN), starting from day 23 after model induction and continuing for 67 days. AGN 195183 significantly reduced protein excretion and blood pressure, improved histological indices such as the glomerulosclerosis index, glomerular and interstitial cell counts, and interstitial area, and reduced glomerular macrophage infiltration and the gene expression of TGF-β1 and Prepro-ET-1[6]. AGN 195183 (4, 12, 36mg/kg/day; for 20 days) was administered daily by gavage to 2-month-old female CD-1 mice subcutaneously implanted with a Matrigel/rhBMP-2 mixture. AGN 195183 significantly inhibited the formation of ectopic bone-like tissue, reduced mineralized tissue volume, cartilage and bone content, the number of TRAP-positive osteoclasts and vascularization, and downregulated the expression of key chondrogenic and osteogenic genes such as Sox9, Runx2, and VEGFα[7].
References:
[1] Wang Q, Lee D, Sysounthone V, et al. 1,25-dihydroxyvitamin D3 and retonic acid analogues induce differentiation in breast cancer cells with function- and cell-specific additive effects. Breast Cancer Res Treat. 2001 May;67(2):157-68.
[2] Chee LC, Hendy J, Purton LE, et al. ATRA and the specific RARα agonist, NRX195183, have opposing effects on the clonogenicity of pre-leukemic murine AML1-ETO bone marrow cells. Leukemia. 2013 Jun;27(6):1369-80.
[3] Herbert KE, Walkley CR, Winkler IG, et al. Granulocyte colony-stimulating factor and an RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells. Transplantation. 2007 Feb 27;83(4):375-84.
[4] Beard RL, Duong TT, Teng M, et al. Synthesis and biological activity of retinoic acid receptor-alpha specific amides. Bioorg Med Chem Lett. 2002 Nov 4;12(21):3145-8.
[5] Brown G, Marchwicka A, Cunningham A, et al. Antagonizing Retinoic Acid Receptors Increases Myeloid Cell Production by Cultured Human Hematopoietic Stem Cells. Arch Immunol Ther Exp (Warsz). 2017 Feb;65(1):69-81.
[6] Schaier M, Liebler S, Schade K, et al. Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat. J Mol Med (Berl). 2004 Feb;82(2):116-25.
[7] Shimono K, Morrison TN, Tung WE, et al. Inhibition of ectopic bone formation by a selective retinoic acid receptor alpha-agonist: a new therapy for heterotopic ossification? J Orthop Res. 2010 Feb;28(2):271-7.
AGN 195183是一种具有口服活性的维甲酸受体α（RARα）选择性激动剂[1-2]。AGN 195183对RARα具有高亲和力（Kd=3nM），对RARβ/γ无活性。AGN 195183可用于急性髓性白血病、多发性骨髓瘤和乳腺癌的相关研究[3]。
在体外，AGN 195183（0-1μM）处理ER阳性人乳腺癌细胞系T-47D和ER阴性人乳腺癌细胞系SK-BR-3 1-8天。AGN 195183显著抑制细胞生长[4]。AGN 195183（100nM）处理人早幼粒细胞白血病细胞系NB-4 96小时，可有效诱导中性粒细胞分化；AGN 195183（100nM）与10nM 1,25-二羟基维生素D3联合处理NB-4细胞96小时，可有效诱导单核细胞分化[5]。
在体内，AGN 195183（4mg/kg/天及20mg/kg/天）口服处理，用于从造模后第23天开始、持续67天治疗肾小球肾炎（Thy-GN）的Wistar大鼠。AGN 195183显著降低了蛋白质排泄和血压，改善了肾小球硬化指数、肾小球及间质细胞计数、间质面积等组织学指标，并减少了肾小球巨噬细胞浸润及TGF-β1、Prepro-ET-1的基因表达[6]。AGN 195183（4、12、36mg/kg/天）通过灌胃每天给药，用于处理皮下植入Matrigel/rhBMP-2混合物的2月龄雌性CD-1小鼠，连续20天。AGN 195183显著抑制了异位骨样组织的形成，减少了矿化组织体积、软骨和骨含量、TRAP阳性破骨细胞数量及血管分布，并下调了Sox9、Runx2、VEGFα等成软骨和成骨关键基因的表达[7]。