KD 5170

KD 5170 is a novel inhibitor of histone deacetylase with IC50 value of 0.045 μM [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.

KD 5170 is an inhibitor of histone deacetylase and inhibited recombinant HDAC enzymes with IC50 values of 0.020, 2.0, 0.075, 0.026, 0.014 μM for HADC1, HADC2, HADC3, HADC4 and HADC6, respectively. In HeLa cell, KD5170 resulted in histone hyperacetylation with an EC50 of 25 nM in a concentration-dependent way. In HCT-116 cells, KD 5170 induced p21WAF1 expression and histone H3 and a-tubulin acetylation [1][2]. In both HL-60 leukemia cells and HCT-116 colorectal cancer cells, KD5170 resulted in cell death in a concentration-dependent way [1].

In mice bearing HCT-116 xenograft tumors, KD 5170 significantly inhibited tumor growth [1]. In mice bearing H929 xenograft tumors, KD 5170 decreased tumor volume and significantly prolonged the mean time to endpoint. Also, the increase of histone acetylation was found in spleen and tumor tissues of the mice treated with KD 5170 [3].

References:
[1].  Hassig CA, Symons KT, Guo X, et al. KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo. Mol Cancer Ther, 2008, 7(5): 1054-1065.
[2].  Payne JE, Bonnefous C, Hassig CA, et al. Identification of KD5170: a novel mercaptoketone-based histone deacetylase inhibitor. Bioorg Med Chem Lett, 2008, 18(23): 6093-6096.
[3].  Feng R, Ma H, Hassig CA, et al. KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling. Mol Cancer Ther, 2008, 7(6): 1494-1505.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling.[Pubmed:18566220]

Mol Cancer Ther. 2008 Jun;7(6):1494-505.

Histone deacetylase inhibitors have emerged as promising anticancer drugs. Using an unbiased ultrahigh throughput screening system, a novel mercaptoketone-based histone deacetylase inhibitor series was identified that was optimized to the lead compound, KD5170. KD5170 inhibited the proliferation of myeloma cell lines and the viability of CD138(+) primary myeloma cells by induction of apoptosis, accompanied by an increase of acetylation of histones and activation of caspase-3, caspase-8, and caspase-9. Treatment with KD5170 caused a loss of mitochondrial membrane potential resulting in release of apoptogenic factors such as cytochrome c, Smac, and apoptosis-inducing factor. Furthermore, KD5170 induced oxidative stress and oxidative DNA damage in myeloma cells as evidenced by the up-regulation of heme oxygenase-1 and H2A.X phosphorylation. Combination of KD5170 with proteasome inhibitor bortezomib or tumor necrosis factor-related apoptosis-inducing ligand synergistically enhanced the antimyeloma activity. We further found that resistance of myeloma cells to KD5170 was associated with activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase pathway under treatment with KD5170. Pretreatment with the mitogen-activated protein kinase inhibitor U0126 restored sensitivity to KD5170, suggesting that the combination of KD5170 with U0126 could overcome drug resistance. Growth of myeloma tumor xenografts in KD5170-treated nude mice was significantly inhibited and survival was prolonged. Histone acetylation was increased in spleen and tumor tissues of animals treated with KD5170. Our data indicate that KD5170 has potent antimyeloma activity in vitro and in vivo, which is mediated by DNA damage and mitochondrial signaling and subsequent induction of apoptosis.

Identification of KD5170: a novel mercaptoketone-based histone deacetylase inhibitor.[Pubmed:18954983]

Bioorg Med Chem Lett. 2008 Dec 1;18(23):6093-6.

We report the identification of KD5170, a potent mercaptoketone-based Class I and II-histone deacetylase inhibitor that demonstrates broad spectrum cytotoxic activity against a range of human tumor-derived cell lines. KD5170 exhibits robust and sustained histone H3 hyperacetylation in HCT-116 xenograft tumors following single oral or i.v. dose and inhibition of tumor growth following chronic dosing.

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo.[Pubmed:18483295]

Mol Cancer Ther. 2008 May;7(5):1054-65.

Histone deacetylase (HDAC) inhibitors have garnered significant attention as cancer drugs. These therapeutic agents have recently been clinically validated with the market approval of vorinostat (SAHA, Zolinza) for treatment of cutaneous T-cell lymphoma. Like vorinostat, most of the small-molecule HDAC inhibitors in clinical development are hydroxamic acids, whose inhibitory activity stems from their ability to coordinate the catalytic Zn2+ in the active site of HDACs. We sought to identify novel, nonhydroxamate-based HDAC inhibitors with potentially distinct pharmaceutical properties via an ultra-high throughput small molecule biochemical screen against the HDAC activity in a HeLa cell nuclear extract. An alpha-mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC50 of 0.045 micromol/L in the screening biochemical assay and an EC50 of 0.025 micromol/L in HeLa cell-based assays that monitor histone H3 acetylation. KD5170 also exhibits broad spectrum classes I and II HDAC inhibition in assays using purified recombinant human isoforms. KD5170 shows significant antiproliferative activity against a variety of human tumor cell lines, including the NCI-60 panel. Significant tumor growth inhibition was observed after p.o. dosing in human HCT-116 (colorectal cancer), NCI-H460 (non-small cell lung carcinoma), and PC-3 (prostate cancer) s.c. xenografts in nude mice. In addition, a significant increase in antitumor activity and time to end-point occurred when KD5170 was combined with docetaxel in xenografts of the PC-3 prostate cancer cell line. The biological and pharmaceutical profile of KD5170 supports its continued preclinical and clinical development as a broad spectrum anticancer agent.