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.