Design, synthesis and biological evaluation of novel c-Met/HDAC dual inhibitors

  • Bioorg Med Chem Lett. 2020 Dec 1;30(23):127610. doi: 10.1016/j.bmcl.2020.127610.
Yuhong Dong  1 ,  Hao Hu  1 ,  Yuwei Sun  1 ,  Mingze Qin  1 ,  Ping Gong  1 ,  Yunlei Hou  2 ,  Yanfang Zhao  3
Affiliations
  • 1. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China.
  • 2. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: [email protected].
  • 3. Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, PR China. Electronic address: [email protected].
PMID: 33045329 DOI: 10.1016/j.bmcl.2020.127610
Abstract

In this work three novel series of c-Met/HDAC bifunctional inhibitors were designed and synthesized by merging pharmacophores of c-Met and HDAC inhibitors. The most potent compound 11j inhibited c-Met kinase and HDAC1 with IC50 values of 21.44 and 45.22 nM, respectively. In addition, 11j showed efficient antiproliferative activities against both MCF-7 and A549 cells with greater potency than the reference drug SAHA and Cabozantinib. This work may lay the foundation for developing novel dual c-Met/HDAC inhibitors as potential Anticancer therapeutics.

Keywords
Antitumor activity; Design; HDAC; Synthesis; c-Met.