ACY-1215

ACY-1215 is an inhibitor of the class IIb histone deacetylase (HDAC) HDAC6 (IC₅₀ = 0.0047 µM).¹ It is selective for HDAC6 over the class I HDACs HDAC1, -2, -3, and -8 (IC₅₀s = 0.058, 0.048, 0.051, and 0.1 µM, respectively), class IIa HDACs HDAC4, -5, -7, and -9 (IC₅₀s = 7, 5, 1.4 and >10 µM, respectively), class III HDACs sirtuin 1 (SIRT1) and SIRT2 (IC₅₀s = >10 µM for both), and the class IV HDAC HDAC11 (IC₅₀ = >10 µM). ACY-1215 (0.5-2.5 µM) induces accumulation of acetylated α-tubulin in OCI-LY10 diffuse large B cell lymphoma (DLBCL) cells and induces cytotoxicity in several multiple myeloma cell lines (IC₅₀s = 2-8 µM).^2,1 It decreases tumor volume and increases survival in an OCI-LY10 mouse xenograft model when administered at a dose of 50 mg/kg in combination with the 20S proteasome inhibitor bortezomib (Item No. 10008822).² ACY-1215 also decreases liver and kidney cyst area and liver fibrosis in PCK rats in a model of polycystic liver disease.³

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1. Santo, L., Hideshima, T., Kung, A.L., et al. Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma. Blood 119(11), 2579-2589 (2012).

2. Amengual, J.E., Johannet, P., Lombardo, M., et al. Dual targeting of protein degradation pathways with the selective HDAC6 inhibitor ACY-1215 and bortezomib is synergistic in lymphoma. Clin. Cancer Res. 21(20), 4663-4675 (2015).

3. Gradilone, S.A., Habringer, S., Masyuk, T.V., et al. HDAC6 is overexpressed in cystic cholangiocytes and its inhibition reduces cystogenesis. Am. J. Pathol. 184(3), 600-608 (2014).