Y-320, a potent phenylpyrazoleanilide immunomodulator, is recognized for its oral activity. It suppresses IL-17 production by CD4 T cells stimulated with IL-15, presenting IC50 values ranging from 20 to 60 nM. This compound also bolsters TP53, DMD, and COL17A1 PTC readthrough alongside G418, elevating both cellular protein levels and protein synthesis. When used with a low dosage of Paclitaxel, Y-320 notably increases the sensitivity of multidrug resistance (MDR) tumors to the drug, triggering G2/M phase arrest and apoptosis. Y-320's applications extend to rheumatoid arthritis (RA) and cancer research[1].[2].
体内研究
In vivo, Y-320 at doses up to 3 mg/kg administered orally daily for 42 days ameliorates collagen-induced arthritis (CIA) in DBA/1J mice, reducing IL-17 mRNA expression in arthritic joints[1].
Furthermore, at a dosage of 5 mg/kg intravenously every three days for 18 days, Y-320 sensitizes MDR xenograft tumors to Paclitaxel in homogenous nude athymic mice bearing Bats-72 xenografts[3].
体外研究
In both murine and human CD4 T cells stimulated with IL-15, Y-320 demonstrates inhibitory effects on IL-17 production, with IC50 values identified as 25.7, 52.4, and 57.4 nM for murine CD4 T cells, murine Th17 cells, and human CD4 T cells, respectively, over a 48-hour period at concentrations up to 100 nM[1]. Otherwise, Y-320 also inhibits phosphorylation of JAK1/JAK3 in murine CD4 T cells stimulated with IL-15/CXCL12/anti-CD3 mAb[1].
At concentrations ranging from 0.25 to 2 μM over 48 hours, Y-320 enhances PTC readthrough in various cell lines and increases cellular protein levels and ribosome biogenesis in a concentration-dependent manner[2].
Y-320 (0-2 μM; 48 h; Tsc2-/- cells) causes a small decrease in phospho-S6K combination with G418 (100 μM)[2].
Additionally, at 1 μM over 48 hours, Y-320 up-regulates the expression of several CXC chemokines, including CXCL10, CXCL8, and CXCL2, in HDQ-P1 cells[2].
Y-320, at a dose of 500 nM for 72 hours, reverses paclitaxel resistance in MDR cancer cells, with reversal indices (RI) when combined with Paclitaxel ranging from 1.7 to 9.4 in different cell lines. It enhances paclitaxel-induced G2/M arrest and apoptosis in Bads-200 cells[3].
Additionally, Y-320 serves as a substrate of P-gp and reverses MDR by inhibiting P-gp function[3].
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