Computational Identification of HDAC6-Targeted Inhibitor Candidates for Cancer Therapy
Authors
Vihan Bhattacharjee
Share
Annotation
Cancer continues to impact millions of people worldwide and incur significant economic costs despite advances in modern therapeutics. Precision medicine offers a promising approach to overcome the harmful off-target impacts on healthy tissue of conventional therapies. In particular, HDAC6 is an attractive therapeutic target due to its pivotal role in facilitating tumor growth. This study employs a comprehensive computational framework to identify potential HDAC6 inhibitor candidates to accelerate early-stage drug discovery. First, binding sites were identified
within the HDAC6 structure to determine its suitability for binding with small molecules. Then, pharmacophore modeling identified molecular features required for favorable interactions with the HDAC6 binding pocket. The resulting compounds underwent molecular docking to determine their predicted binding affinities. Then, the pharmacokinetic properties and toxicity of the remaining compounds were analyzed to identify the compounds that best balanced favorable interactions with the HDAC6 binding site, suitable pharmacokinetic properties, and minimal predicted safety liabilities. Based upon this workflow, Molport-023-219-174 was determined to be the lead compound and Molport-035-800-274 was a promising backup compound. The integration of these computational processes streamlined the early-stage drug discovery pipeline, enabling the efficient identification of promising HDAC6 inhibitors and providing a foundation for drug-discovery workflows.
Keywords
Authors
Vihan Bhattacharjee
Share
References:
Al Meslamani, A. Z. (2023). The future of precision medicine in oncology. Expert Review of Precision Medicine and Drug Development, 8(1), 43–47. https://doi.org/10.1080/ 23808993.2023.2292988
Chen, P., & Zhang, Y. (2026). Role of HDAC6 in carcinomas. Discover Oncology, 17(1), Article 4391. https://doi.org/10.1007/s12672-026-04391-9
Chen, S., Cao, Z., Prettner, K., Kuhn, M., Yang, J., Jiao, L., Wang, Z., Li, W., Geldsetzer, P., Bärnighausen, T., Bloom, D. E., & Wang, C. (2023). Estimates and projections of the global economic cost of 29 cancers in 204 countries and territories from 2020 to 2050. JAMA Oncology, 9(4), 465–472. https://doi.org/10.1001/jamaoncol.2022.7826
Ediriweera, M. K., Tennekoon, K. H., & Samarakoon, S. R. (2021). Odd-chain fatty acids reduce histone deacetylase 6 (HDAC6) expression and inhibit proliferation in human breast and lung cancer cells. Biochimie, 181, 194–207. https://ueaeprints.uea.ac.uk/id/eprint/ 75951/
GBD 2023 Cancer Collaborators. (2025). The global, regional, and national burden of cancer, 1990–2023, with forecasts to 2050: a systematic analysis for the Global Burden of Disease Study 2023. The Lancet, 406(10512), 1565–1586. https://doi.org/10.1016/ S0140-6736(25)01635-6
Harding, R. J., Franzoni, I., & Structural Genomics Consortium. (2023). Discovery and characterization of a chemical probe targeting the zinc-finger ubiquitin-binding domain of HDAC6. Journal of Medicinal Chemistry, 66(5), 3466–3479. https://doi.org/10. 1021/acs.jmedchem.3c00314
Ho, T. C. B., Chan, A. H. Y., & Ganesan, A. (2020). Thirty years of HDAC inhibitors: 2020 hindsight. Medicinal Research Reviews, 40(6), 2153–2194. https://doi.org/10.1002/ med.21682
Huang, Z., Li, L., Cheng, B., & Li, D. (2024). Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies. Biomedicine & Pharmacotherapy, 178, Article 117218. https://doi.org/10.1016/j.biopha.2024.117218
Kouidhi, S., Elgaaied, A. B., & Chouaib, S. (2024). Impact of metabolic reprogramming on the immune response in the tumor microenvironment. Cancer Immunology, Immunotherapy, 73(4), Article 68. https://pmc.ncbi.nlm.nih.gov/articles/PMC12021777/
Lipinski, C. A., Lombardo, F., Dominy, B. W., & Feeney, P. J. (2001). Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Advanced Drug Delivery Reviews, 46(1–3), 3–26. https://doi. org/10.1016/S0169-409X(00)00129-0
Liu, W., Guo, Z., Sun, S., et al. (2026). Discovery of potent HDAC6-selective inhibitors based on artemisinin: Design, synthesis, and antitumor evaluation. Journal of Medicinal Chemistry. Advance online publication. https://doi.org/10.1021/acs.jmedchem.6c00138
Marchetti, P., Curigliano, G., Biffoni, M., et al. (2025). Genomically matched therapy in advanced solid tumors: The randomized phase 2 ROME trial. Nature Medicine, 31, 3514–3523. https://doi.org/10.1038/s41591-025-03918-x
Subramanian, S., Bates, S. E., Wright, J. J., Espinoza-Delgado, I., & Piekarz, R. L. (2010). Clinical toxicities of histone deacetylase inhibitors. Pharmaceuticals, 3(9), 2751–2767. https://doi.org/10.3390/ph3092751
Sung, H., Ferlay, J., Siegel, R. L., Laversanne, M., Soerjomataram, I., Jemal, A., & Bray, F. (2021). Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 71(3), 209–249. https://doi.org/10.3322/caac.21660
Tsimberidou, A. M., Fountzilas, E., Nikanjam, M., & Kurzrock, R. (2020). Review of precision cancer medicine: Evolution of the treatment paradigm. Cancer Treatment Reviews, 86, Article 102019. https://doi.org/10.1016/j.ctrv.2020.102019
Zafar, A., Khatoon, S., Khan, M. J., Abu, J., & Naeem, A. (2025). Advancements and limitations in traditional anti-cancer therapies: A comprehensive review of surgery, chemotherapy, radiation therapy, and hormonal therapy. Discover Oncology, 16(1), Article 607. https:
Other articles of the issue
