Ricolinostat

Ricolinostat (ACY-1215) is a potent and selective HDAC6 inhibitor, with an IC₅₀ of 5 nM. ACY-1215 also inhibits HDAC1, HDAC2, and HDAC3 with IC₅₀s of 58, 48, and 51 nM, respectively. IC50 & Target: IC50: 5 nM (HDAC6), 58 nM (HDAC1), 48 nM (HDAC2), 51 nM (HDAC3)^[1] In Vitro: Ricolinostat (ACY-1215) has slight activity against HDAC8 (IC₅₀=0.1 μM), and has minimal activity (IC₅₀>1 μM) against HDAC4, HDAC5, HDAC7, HDAC9, HDAC11, Sirtuin1, and Sirtuin2. The effect of Ricolinostat (ACY-1215) on multiple myeloma (MM) cell viability is determined with MTT assays using MM cell lines. Exposure of MM cell lines for 48 hours results in dose-dependent decreased viability, with IC₅₀ values ranging from 2-8μM. Ricolinostat (ACY-1215) demonstrates significant activity in the MM PS-341-resistant cell line (ANBL-6.BR), demonstrating the ability of Ricolinostat (ACY-1215) to overcome PS-341 resistance^[1]. In Vivo: Mice treated with Ricolinostat (ACY-1215), PS-341, or Ricolinostat plus PS-341 show a significant delay in tumor growth (P=0.01, P=0.006, and P<0.0001, respectively). Combined treatment with Ricolinostat and PS-341 shows significant suppression of tumor growth and significantly prolonged overall survival (OS) compare with the control group (17 days in the control vs 40 days in the combination-treated group, P<0.0001) and the Ricolinostat (ACY-1215)-treated group (22 days in the PS-341 group vs 40 days in the combination-treated group, P<0.0001). Weight loss in the combination-treated group is between 4% and 12% compare with the same-day control group values during treatment, with complete recovery after the last injection. As is observed in the plasmacytoma model, a significant therapeutic advantage is found by combining Ricolinostat with PS-341 compare with either agent alone^[1].