TMP269 is a novel and selective inhibitor of class IIa histone deacetylase with IC50 values of 126, 80, 36, 9 nM for HDAC 4, 5, 7, 9, respectively [1].
Histone deacetylases (HADC) are a series of enzymes that remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone and make the histones to wrap the DNA more tightly, which prevent transcription.
TMP269 is a novel and selective class IIa HDAC inhibitor. In MM cell lines, TMP269 induced modest cytotoxicity with IC50 values ranging from 22 to 38 μM in a dose-dependent way, which was associated with cleavage of caspase-3, -8, -9 and PARP. Also, TMP269 enhanced CFZ-induced apoptosis and increased the expression of activating transcription factor 4 (ATF4) and proapoptotic transcription factor C/EBP homologous protein (CHOP). In the presence of BMSCs or IL-6, TMP269 and CFZ also showed significant cytotoxicity [2]. In IEC-18 intestinal epithelial cells, TMP269 inhibited cell proliferation, cell cycle progression and DNA synthesis in response to G protein-coupled receptor/protein kinase D1 (PKD1) activation [3].
References:
[1]. Lobera M, Madauss KP, Pohlhaus DT, et al. Selective class IIa histone deacetylase inhibition via a nonchelating zinc-binding group. Nat Chem Biol, 2013, 9(5): 319-325.
[2]. Kikuchi S, Suzuki R, Ohguchi H, et al. Class IIa HDAC inhibition enhances ER stress-mediated cell death in multiple myeloma. Leukemia, 2015.
[3]. Sinnett-Smith J, Ni Y, Wang J, et al. Protein kinase D1 mediates class IIa histone deacetylase phosphorylation and nuclear extrusion in intestinal epithelial cells: role in mitogenic signaling. Am J Physiol Cell Physiol, 2014, 306(10): C961-71.