2. Academic Validation
  3. Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy

Synthesis and investigation of novel 6-(1,2,3-triazol-4-yl)-4-aminoquinazolin derivatives possessing hydroxamic acid moiety for cancer therapy

  • Bioorg Med Chem. 2017 Jan 1;25(1):27-37. doi: 10.1016/j.bmc.2016.10.006.
Chao Ding 1,  Shaopeng Chen 2,  Cunlong Zhang 3,  Guangnan Hu 4,  Wei Zhang 1,  Lulu Li 2,  Yu Zong Chen 3,  Chunyan Tan 5,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 Shenzhen Technology and Engineering Laboratory for Personalized Cancer Diagnostics and Therapeutics, Shenzhen Kivita Innovative Drug Discovery Institute, Shenzhen 518055, PR China.
  • 4 Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, United States.
  • 5 Department of Chemistry, Tsinghua University, Beijing 100084, PR China; The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: tancy@sz.tsinghua.edu.cn.
  • 6 The State Key Laboratory Breeding Base-Shenzhen Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China. Electronic address: jiangyy@sz.tsinghua.edu.cn.
PMID: 27769671 DOI: 10.1016/j.bmc.2016.10.006
Abstract

By merging the critical pharmacophore of EGFR/HER2 and HDAC inhibitors into one compound, a novel series of EGFR, HER-2, and HDAC multitarget inhibitors were synthesized. Compounds 9a-l contained 4-anilinoquinazolines with C-6 triazole-linked long alkyl chains of hydroxamic acid and displayed excellent inhibition against these Enzymes (compound 9d exhibited the best inhibitory potency on wild-type EGFR, HDAC1, and HDAC6 with IC50 values 0.12nM, 0.72nM and 3.2nM individually). Furthermore, compounds 9b and 9d potently inhibited proliferation of five human Cancer cell lines (with IC50 values between 0.49 and 8.76μM). Further mechanistic study revealed that compound 9d also regulated the phosphorylation of EGFR and HER2 and histone H3 hyperacetylation on the cellular level and induced remarkable Apoptosis in BT-474 cells. Therefore, our study suggested that a system network-based multi-target drug design strategy might provided an alternate drug design method, by taking into account the synergy effect of EGFR, HER-2 and HDAC.

Keywords

EGFR; HDAC; HER2; Multitarget; Resistance; Synergy.

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