2. Academic Validation
  3. Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer

Design, synthesis and biological evaluation of novel HDAC inhibitors with improved pharmacokinetic profile in breast cancer

  • Eur J Med Chem. 2020 Nov 1;205:112648. doi: 10.1016/j.ejmech.2020.112648.
Dahong Yao 1,  Chenyang Li 2,  Jin Jiang 3,  Jian Huang 4,  Jinhui Wang 5,  Zhendan He 6,  Jin Zhang 7
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518060, China; College of Pharmacy, Harbin Medical University, Harbin, 150081, China. Electronic address: [email protected].
  • 2 School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, 518060, China. Electronic address: [email protected].
  • 3 College of Pharmacy, Harbin Medical University, Harbin, 150081, China. Electronic address: [email protected].
  • 4 College of Pharmacy, Harbin Medical University, Harbin, 150081, China; West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. Electronic address: [email protected].
  • 5 College of Pharmacy, Harbin Medical University, Harbin, 150081, China; West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. Electronic address: [email protected].
  • 6 School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518060, China; School of Pharmaceutical Sciences, Guangdong Key Laboratory for Genome Stability & Human Disease Prevention, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, 518060, China. Electronic address: [email protected].
  • 7 School of Pharmaceutical Sciences, Shenzhen Technology University, Shenzhen, 518060, China; West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China. Electronic address: [email protected].
PMID: 32791401 DOI: 10.1016/j.ejmech.2020.112648
Abstract

The dysfunction of histone deacetylase (HDACs) is closely related to tumorigenesis and development, which has been emerged as an attractive drug design target for Cancer therapy. In the present study, we designed and synthesized a series of novel HDAC inhibitors using a substituted quinazoline as the capping group and attaching 3, 5-dimethylbenyl as a potential metabolic site protector. 23g and 23h were demonstrated potent HDAC inhibitory activities and anti-proliferative effects against MDA-MB-231 cells. In addition, 23g and 23h both could significantly increase the acetylation level of intracellular proteins, especially in α-Tubulin and HSP90. 23g and 23h displayed a slight different anti-tumor mechanism, 23g mainly induced Apoptosis while 23h induced obviously ER-Stress. Furthermore, 23g and 23h both induced Autophagy and migration inhibition. In pharmacokinetics assay, 23g showed a significant improvement of pharmacokinetic profile for oral administration. Additionally, 23g presented more potent anti-proliferation and anti-migration activity than SAHA in zebrafish MDA-MB-231 cell line-derived xenograft model. Together, these results demonstrate that 23g is a novel oral HDAC Inhibitor with a potential capacity of treating breast Cancer.

Keywords

Apoptosis; Autophagy; Breast cancer; HDAC inhibitor; Migration; Pharmacokinetic profile.

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