Cancer Network Disruption by a Single Molecule Inhibitor Targeting Both Histone Deacetylase Activity and Phosphatidylinositol 3-Kinase Signaling
Published version of a preprint
Abstract
Purpose: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells. Experimental Design: We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action. Results: CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells. Conclusions: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks. Clin Cancer Res; 18(15); 4104–13. ©2012 AACR.
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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 [47]
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Histone deacetylases and their inhibitors in cancer, neurological diseases and immune disorders
Falkenberg, K. J., & Johnstone, R. W. (2014) · Nature Reviews Drug Discovery · doi:10.1038/nrd4360 · Cited by 1,564 · see citing works
Targeting histone deacetylases for cancer therapy: Trends and challenges
Liang, T., Wang, F., Elhassan, R. M., Cheng, Y., Tang, X., Chen, W., Fang, H., & Hou, X. (2023) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2023.02.007 · Cited by 222 · see citing works
Development of the first small molecule histone deacetylase 6 (HDAC6) degraders
Yang, K., Song, Y., Xie, H., Wu, H., Wu, Y.-T., Leisten, E. D., & Tang, W. (2018) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2018.05.057 · Cited by 190 · see citing works
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Recent advances of dual FGFR inhibitors as a novel therapy for cancer
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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
“For example, trichostatin A contains a chain of sp2-hybridized carbons for a linker while fimepinostat and quisinostat contain pyrimidines as linkers, yet all 3 molecules inhibit HDACs 1–3 in the picomolar range (Figure 6A) [43, 44, 48].”
Background
- Authors
- Qian, C., Lai, C.-J., Bao, R., Wang, D.-G., Wang, J., Xu, G.-X., Atoyan, R., Qu, H., Yin, L., Samson, M., Zifcak, B., Ma, A. W. S., DellaRocca, S., Borek, M., Zhai, H.-X., Cai, X., & Voi, M.
- Affiliations
- Curis (United States) (US)
- Venue
- Clinical Cancer Research
- Published
- 2012-07-30
- Volume
- 18
- Issue
- 15
- Pages
- 4104-4113
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2107661677
- Cited by
- 248
- References
- 3
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 15 · 2023: 23 · 2022: 20 · 2021: 20 · 2020: 33 · 2019: 23 · 2018: 17 · 2017: 15 · 2016: 20 · 2015: 10 · 2014: 10 · 2013: 2 · 2012: 3
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Clinical Cancer Research (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 › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- CUDC-907, histone deacetylase inhibitors, PI3K inhibitors, class I PI3K, PI3K/AKT/mTOR pathway, STAT3 signaling, receptor tyrosine kinase, epigenetic modifications, synergistic cancer therapy, apoptosis, anticancer activity
- MeSH terms
- Vorinostat, Phosphoinositide-3 Kinase Inhibitors, Animals, Cell Cycle, Enzyme Activation, Enzyme Inhibitors, Female, Histone Deacetylases, Humans, Hydroxamic Acids, Mice, Nude, Morpholines, Neoplasms, Pyrimidines, Quinazolines, Blotting, Western, Signal Transduction, Mice, SCID, Apoptosis, Xenograft Model Antitumor Assays, HCT116 Cells, Cell Line, Tumor, Tumor Burden, Cell Proliferation, Mice, Caspase 3, Histone Deacetylase Inhibitors, Phosphatidylinositol 3-Kinase, Sf9 Cells
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