CRA-024781: a novel synthetic inhibitor of histone deacetylase enzymes with antitumor activity in vitro and in vivo
Abstract
CRA-024781 is a novel, broad spectrum hydroxamic acid–based inhibitor of histone deacetylase (HDAC) that shows antitumor activity in vitro and in vivo preclinically and is under evaluation in phase I clinical trials for cancer. CRA-024781 inhibited pure recombinant HDAC1 with a Ki of 0.007 μmol/L, and also inhibited the other HDAC isozymes HDAC2, HDAC3/SMRT, HDAC6, HDAC8, and HDAC10 in the nanomolar range. Treatment of cultured tumor cell lines grown in vitro with CRA-024781 resulted in the accumulation of acetylated histone and acetylated tubulin, resulting in an inhibition of tumor cell growth and the induction of apoptosis. CRA-024781 parenterally administered to mice harboring HCT116 or DLD-1 colon tumor xenografts resulted in a statistically significant reduction in tumor growth at doses that were well tolerated as measured by body weight. Inhibition of tumor growth was accompanied by an increase in the acetylation of α-tubulin in peripheral blood mononuclear cells, and an alteration in the expression of many genes in the tumors, including several involved in apoptosis and cell growth. These results reveal CRA-024781 to be a novel HDAC inhibitor with potent antitumor activity. [Mol Cancer Ther 2006;5(5):1309–17]
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The majority of hydroxamate HDACi have a propensity to act in a pan-inhibitory fashion.
“The majority of hydroxamate HDACi have a propensity to act in a pan-inhibitory fashion (Figure 6A) [42–49].”
From Medicinal chemistry advances in targeting class I histone deacetylases (2023) · cites this paper as [46]
Cites
In vivo destabilization of dynamic microtubules by HDAC6‐mediated deacetylation
Matsuyama, A., Shimazu, T., Sumida, Y., Saito, A., Yoshimatsu, Y., Seigneurin‐Berny, D., Osada, H., Komatsu, Y., Nishino, N., Khochbin, S., et al. (2002) · The EMBO Journal · doi:10.1093/emboj/cdf682 · Cited by 720 · see citing works
Cloning and characterization of a novel human histone deacetylase, HDAC8
BUGGY, J. J., SIDERIS, M. L., MAK, P., LORIMER, D. D., MCINTOSH, B., & CLARK, J. M. (2000) · Biochemical Journal · doi:10.1042/bj3500199 · Cited by 197 · see citing works
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HDACs, histone deacetylation and gene transcription: from molecular biology to cancer therapeutics
Gallinari, P., Marco, S. D., Jones, P., Pallaoro, M., & Steinkühler, C. (2007) · Cell Research · doi:10.1038/sj.cr.7310149 · Cited by 678 · see citing works
Balasubramanian, S., Ramos, J., Luo, W., Sirisawad, M., Verner, E., & Buggy, J. J. (2008) · Leukemia · doi:10.1038/leu.2008.9 · Cited by 458 · see citing works
Self-citationMedicinal chemistry advances in targeting class I histone deacetylases
Abdallah, D. I., de Araujo, E. D., Patel, N. H., Hasan, L. S., Moriggl, R., Krämer, O. H., & Gunning, P. T. (2023) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2023.00166 · Cited by 15 · see citing works
“An interesting observation is the presence of free-amine and N-heterocycles in the cap region across multiple inhibitors (e.g., fimepinostat, quisinostat, HDAC-IN-30, and pracinostat), which may be contributing to increased affinity towards HDAC.”
Background
- Authors
- Buggy, J. J., Cao, Z. A., Bass, K. E., Verner, E., Balasubramanian, S., Liu, L., Schultz, B. E., Young, P. R., & Dalrymple, S. A.
- Affiliations
- Celera Genomics, South San Francisco, California
- Venue
- Molecular Cancer Therapeutics
- Published
- 2006-05-01
- Volume
- 5
- Issue
- 5
- Pages
- 1309-1317
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- OpenAlex
- W2102376919
- Cited by
- 127
- References
- 2
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 7 · 2020: 11 · 2019: 3 · 2018: 2 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 9 · 2013: 9 · 2012: 3
- FWCI
- 4.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Keywords
- histone deacetylase inhibitors, hydroxamic acids, HDAC1, HDAC2, HDAC6, HDAC8, HDAC10, anticancer activity, colon cancer, tumor xenografts, apoptosis, histone acetylation, alpha-tubulin acetylation, gene expression changes
- MeSH terms
- Acetylation, Animals, Antineoplastic Agents, Benzofurans, Enzyme Inhibitors, Female, Histone Deacetylases, Histones, Humans, Hydroxamic Acids, Mice, Inbred BALB C, Poly(ADP-ribose) Polymerases, Transcription, Genetic, Tumor Cells, Cultured, Biomarkers, Tumor, Drug Design, HCT116 Cells, Cell Proliferation, Cyclin-Dependent Kinase Inhibitor p21, Mice, Histone Deacetylase Inhibitors, In Vitro Techniques
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