TMP269

TMP269 is a novel and selective class IIa histone deacetylase (HDAC) inhibitor with IC₅₀s of 157 nM, 97 nM, 43 nM and 23 nM for HDAC4, HDAC5, HDAC7 and HDAC9, respectively. IC50 & Target: IC50: 23 nM (HDAC9), 43 nM (HDAC7), 97 nM (HDAC5), 157 nM (HDAC4)^[1] In Vitro: TMP269 has no impact on the mitochondrial activity and/or the viability of human CD4⁺ T cells at 10 μM, and may be used as tools to identify the endogenous substrates of the class IIa HDAC enzymes^[1]. In IEC-18 intestinal epithelial cells, TMP269 prevents cell cycle progression, DNA synthesis, and proliferation induced in response to G protein-coupled receptor/PKD1 activation^[2]. As with HDAC4 knockdown, TMP269 significantly enhances cytotoxicity induced by CFZ in MM cell lines, upregulating ATF4 and CHOP and inducing apoptosis. TMP269 does not hyperacetylate histone H3K9 or α-tubulin in MM cell lines, confirming that it has no inhibitory effects on class I or IIb HDACs. In a dosedependent manner, TPM269-induced cytotoxicity is associated with cleavage of caspase-8, -9, -3 and PARP, consistent with apoptosis^[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].