Design, synthesis, and biological evaluation of quinazoline derivatives as dual HDAC1 and HDAC6 inhibitors for the treatment of cancer

• Published in: Chemical biology & drug design Vol. 93; no. 3; pp. 232 - 241
• Main Authors: Chen, Jinying, Sang, Zitai, Jiang, Youjun, Yang, Chao, He, Linhong
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.03.2019
• Subjects: Acetylation - drug effects; Animals; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Biochemistry & Molecular Biology; cancer; Cell Line, Tumor; Cell Proliferation - drug effects; Chemistry, Medicinal; Drug Design; dual inhibitors; HDAC; Histone Deacetylase 1 - antagonists & inhibitors; Histone Deacetylase 1 - metabolism; Histone Deacetylase 6 - antagonists & inhibitors; Histone Deacetylase 6 - metabolism; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - metabolism; Life Sciences & Biomedicine; Mice; Neoplasms; Pharmacology & Pharmacy; Quinazolines - chemistry; Quinazolines - metabolism; Quinazolines - pharmacology; Quinazolines - therapeutic use; SAR study; Science & Technology; Structure-Activity Relationship; Transplantation, Heterologous; Tubulin - metabolism; cancer; SAR study; HISTONE DEACETYLASE INHIBITORS; dual inhibitors; HDAC
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13405

Fifty‐eight quinazoline‐based compounds were designed and synthesized based on the structural optimizations from the lead compound 23bb in an attempt to search for more potent dual HDAC1 and HDAC6 inhibitors. Among them, 32c (HDAC1, IC50 = 31.10 ± 0.37 nM; HDAC6, IC50 = 16.15 ± 0.62 nM) and 32d (HDAC1, IC50 = 37.00 ± 0.24 nM; HDAC6, IC50 = 35.00 ± 0.71 nM) were not only identified as potent dual‐acting HDAC1 and HDAC6 inhibitors with over 10‐fold selectivity to the other HDACs, but also displayed activities in tubulin acetylation and histone H3 acetylation induction. Importantly, both of them displayed strong antiproliferative activities against various tumor cell lines in vitro with IC50 values less than 40 nM, especially for hematologic tumors cells (U266 and RPMI8226, IC50 < 1 nM), which were even better than 23bb and SAHA. Furthermore, 32c showed a significant tumor growth inhibition (antitumor rate = 63.98%, p < 0.05) in the resistant MCF‐7/ADR xenograft model without any obvious body weight changes and abnormal behaviors. Our findings validate that 32c is a potent dual inhibitor of HDAC1/6 that can be an efficacious treatment for breast cancer with Adriamycin resistance. Fifty‐eight quinazoline‐based compounds were designed and synthesized based on the structural optimization from the lead compound 23bb in an attempt to search for more potent dual HDAC1 and HDAC6 inhibitors. Among them, 32c not only displayed favorable inhibition to HDAC1 (IC50 = 31.10 ± 0.37 nM) and HDAC6 (IC50 = 16.15 ± 0.62 nM), but also exhibited strong antiproliferative activities against various tumor cell lines in vitro with IC50 values less than 4 nM, including solid tumors (HCT116, HepG2, M‐M‐231, MCF‐7, H460, H1975, and Hela cells) and hematologic tumors (U266 and RPMI8226 cells). Additionally, 32c also can significantly reduce the resistant MCF‐7/ADR xenograft tumor to grow with an antitumor rate of 63.98% (p < 0.05), and all the treated mice appeared to be normal without any body weight changes and abnormal behaviors observed. Thus, as a potent and dual inhibitor of HDAC1/6, 32c has the potential to be an efficacious treatment for breast cancer with Adriamycin resistant.