2. Academic Validation
  3. Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment

Design, synthesis and evaluation of acridine derivatives as multi-target Src and MEK kinase inhibitors for anti-tumor treatment

  • Bioorg Med Chem. 2016 Jan 15;24(2):261-9. doi: 10.1016/j.bmc.2015.12.011.
Zhishan Cui 1,  Xi Li 2,  Lulu Li 1,  Bin Zhang 3,  Chunmei Gao 4,  Yuzong Chen 5,  Chunyan Tan 1,  Hongxia Liu 1,  Weiyi Xie 2,  Ti Yang 2,  Yuyang Jiang 6
Affiliations

Affiliations

  • 1 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 2 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China.
  • 3 National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: binzhang86@126.com.
  • 4 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China. Electronic address: chunmeigao@sz.tsinghua.edu.cn.
  • 5 Bioinformatics and Drug Design Group, Department of Pharmacy, Centre for Computational Science and Engineering, 117543 Singapore, Singapore.
  • 6 The Guangdong Province Key Laboratory of Chemical Biology, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; National & Local United Engineering Lab for Personalized Anti-tumor Drugs, The Graduate School at Shenzhen, Tsinghua University, Shenzhen 518055, PR China; School of Medicine, Tsinghua University, Beijing 100084, PR China.
PMID: 26707846 DOI: 10.1016/j.bmc.2015.12.011
Abstract

Clinical studies have shown enhanced Anticancer effects of combined inhibition of Src and MEK kinases. Development of multi-target drugs against Src and MEK is of potential therapeutic advantage against cancers. As a follow-up of our previous studies, and by using molecular docking method, we designed and synthesized a new series of 9-anilinoacridines containing phenyl-urea moieties as potential novel dual Src and MEK inhibitors. The anti-proliferative assays against K562 and HepG-2 tumor cells showed that most of the derivatives displayed good cytotoxicity in vitro. In particular, kinase inhibition assays showed that compound 8m inhibited Src (59.67%) and MEK (43.23%) at 10 μM, and displayed moderate inhibitory activity against ERK and Akt, the downstream effectors of both Src and MEK. Moreover, compound 8m was found to induce K562 cells Apoptosis. Structure-activity relationships of these derivatives were analyzed. Our study suggested that acridine scaffold, particularly compound 8m, is of potential interest for developing novel multi-target Src and MEK kinase inhibitors.

Keywords

Acridine; Antitumor; Apoptosis; Kinase inhibitor; MEK; Src.

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