Uses
TMP269 is a selective class IIa histone deacetylase (HDAC) inhibitor via a non chelating zinc-binding group.
Biological Activity
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].
in vivo
In vivo angiogenesis assay, MDA-MB-231 cells are mixed with growth factor-reduced Matrigel and implanted subcutaneously into the flanks of nude mice. TMP269 (subcutaneous injection; 15 mg/kg; every other day; 10 days) shows an obvious antiangiogenic effect with 76% inhibition of angiogenesis in mice[4].
IC 50
HDAC9: 23 nM (IC50); HDAC7: 43 nM (IC50); HDAC5: 97 nM (IC50); HDAC4: 157 nM (IC50); HDAC8: 42000 nM (IC50); HDAC6: 82000 nM (IC50)
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.
