2. Academic Validation
  3. Quinazoline-based hydroxamic acid derivatives as dual histone methylation and deacetylation inhibitors for potential anticancer agents

Quinazoline-based hydroxamic acid derivatives as dual histone methylation and deacetylation inhibitors for potential anticancer agents

  • Bioorg Med Chem. 2022 Jan 1;53:116524. doi: 10.1016/j.bmc.2021.116524.
Haoting Zheng 1,  Qiuzi Dai 1,  Zigao Yuan 2,  Tingting Fan 3,  Cunlong Zhang 4,  Zijian Liu 4,  Bizhu Chu 5,  Qinsheng Sun 6,  Yan Chen 7,  Yuyang Jiang 8
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
  • 2 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China.
  • 4 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 5 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, PR China.
  • 6 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Life Sciences, Tsinghua University, 100084 Beijing, PR China.
  • 7 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, Shenzhen Kivita Innovative Drug Discovery Institute, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Life Sciences, Tsinghua University, 100084 Beijing, PR China. Electronic address: [email protected].
  • 8 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The State Key Laboratory of Chemical Oncogenomics, Key Laboratory of Chemical Biology, Tsinghua Shenzhen International Graduate School, Tsinghua University, Shenzhen, Guangdong 518055, PR China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Shenzhen, Guangdong 518055, PR China; School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, PR China. Electronic address: [email protected].
PMID: 34847495 DOI: 10.1016/j.bmc.2021.116524
Abstract

Cancer is a common malignant disease with complex signaling networks, which means it is unmanageable to Cancer therapy by using single classical targeted drug. Recently, dual- or multitarget drugs have emerged as a promising option for Cancer therapies. Although many multifunctional compounds targeting HDAC have been validated, as far as we know, there is no molecule targeting GLP and HDAC synchronously. In the present work, we designed and synthesized a series of quinazoline-based hydroxamic acid derivatives as dual GLP and HDAC inhibitors. These hybrid compounds showed potent enzymatic inhibitory activities against GLP and HDAC1/6 with IC50 values in the nanomolar range of less than 190 nM. Furthermore, most of our compounds displayed significant broad spectrum cytotoxic activities apart from D3 and D8 against all the tested Cancer cells with IC50 values less than 50 μM. D1, D6 and D7 showed more potent cytotoxic activities than D2, D4 and D5 in those Cancer cells. Especially, compound D7 showed potent inhibitory potency activity against both GLP and HDAC1/6 with IC50 values of 1.3, 89, 13 nM. Besides, D7 exhibited the most potent antiproliferative activity against all the tested Cancer cells. Further evaluations indicated that D7 could inhibit the methylation and deacetylation of H3K9 on protein level. Moreover, D7 could induce Cancer cell Apoptosis, G0/G1 cell cycle arrest, and partly block migration and invasion. All these thorough evaluations warranted D7 as a promising lead compound worth further optimization and development for Cancer therapy.

Keywords

Anticancer; Epigenetic; GLP; HDACs; Multitarget.

Figures
Products