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Research Articles: Therapeutics, Targets, and Development

KD5170, a novel mercaptoketone-based histone deacetylase inhibitor that exhibits broad spectrum antitumor activity in vitro and in vivo

¹ Kalypsys, Inc., San Diego, California, and ² Ida M. and Cecil H. Green Cancer Center, Scripps Green Hospital and Scripps Clinic, La Jolla, California

Requests for reprints: Christian A. Hassig, Kalypsys, Inc., 10420 Wateridge Circle, San Diego, CA 92121.

Abstract

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 -mercaptoketone series was identified and chemically optimized. The lead compound, KD5170, exhibits HDAC inhibitory activity with an IC₅₀ of 0.045 µmol/L in the screening biochemical assay and an EC₅₀ of 0.025 µmol/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. [Mol Cancer Ther 2008;7(5):1054–65]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Current address for J. Hager: Apoptos: 10835 Road to the Cure, San Diego, CA 92121.

³ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

⁴ Hassig CA, Smith ND, and Mager JH, unpublished observation.

⁵ R. Feng, H. Ma, C.A. Hassig, et al. KD5170, a novel mercaptoketone-based HDAC inhibitor, exerts potent anti-myeloma effects by DNA damage and mitochondrial signaling. Molecular Cancer Therapeutics. In press, 2008.

Received 12/ 5/07; revised 2/12/08; accepted 2/12/08.

This article has been cited by other articles:

				R. Feng, H. Ma, C. A. Hassig, J. E. Payne, N. D. Smith, M. Y. Mapara, J. H. Hager, and S. Lentzsch KD5170, a novel mercaptoketone-based histone deacetylase inhibitor, exerts antimyeloma effects by DNA damage and mitochondrial signaling Mol. Cancer Ther., June 1, 2008; 7(6): 1494 - 1505. [Abstract] [Full Text] [PDF]