Target Design of Novel Histone Deacetylase 6 Selective Inhibitors with 2‐Mercaptoquinazolinone as the Cap Moiety

• Main Authors: Bui, H.T.B (Author), Hong, Q.V (Author), Jung, H. (Author), Le, H.T (Author), Nguyen, P.H (Author), Nguyen, Q.C (Author), Nguyen, Q.P (Author), Pham, Q.M (Author), Tran, D.Q (Author), Tran, H.P (Author), Yang, S.-G (Author)
• Format: Article
• Language: English
• Published: MDPI 2022
• Subjects: 2‐mercaptoquinazolinone; anticancer drugs; antineoplastic agent; Antineoplastic Agents; antiproliferative activity; cell proliferation; Cell Proliferation; chemical structure; chemistry; drug screening; Drug Screening Assays, Antitumor; Epigenesis, Genetic; genetic epigenesis; HDAC8 protein, human; histone deacetylase; histone deacetylase 6; Histone Deacetylase 6; histone deacetylase inhibitor; Histone Deacetylase Inhibitors; Histone Deacetylases; human; Humans; hydroxamic acid‐based histone deacetylase inhibitors; metabolism; molecular docking; Molecular Docking Simulation; Molecular Structure; repressor protein; Repressor Proteins; structure activity relation; Structure-Activity Relationship; tubulin acetylation level
• Online Access: View Fulltext in Publisher

 Epigenetic alterations found in all human cancers are promising targets for anticancer therapy. In this sense, histone deacetylase inhibitors (HDACIs) are interesting anticancer agents that play an important role in the epigenetic regulation of cancer cells. Here, we report 15 novel hydroxamic acid‐based histone deacetylase inhibitors with quinazolinone core structures. Five compounds exhibited antiproliferative activity with IC50 values of 3.4–37.8 μM. Compound 8 with a 2‐mercaptoquinazolinone cap moiety displayed the highest antiproliferative efficacy against MCF‐7 cells. For the HDAC6 target selectivity study, compound 8 displayed an IC50 value of 2.3 μM, which is 29.3 times higher than those of HDAC3, HDAC4, HDAC8, and HDAC11. Western blot assay proved that compound 8 strongly inhibited tubulin acetylation, a substrate of HDAC6. Compound 8 also displayed stronger inhibition activity against HDAC11 than the control drug Belinostat. The inhibitory mechanism of action of compound 8 on HDAC enzymes was then explored using molecular docking study. The data revealed a high binding affinity (−7.92 kcal/mol) of compound 8 toward HDAC6. In addition, dock pose analysis also proved that compound 8 might serve as a potent inhibitor of HDAC11. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.