2. Academic Validation
  3. Discovery of novel dual c-Met/HDAC inhibitors as a promising strategy for cancer therapy

Discovery of novel dual c-Met/HDAC inhibitors as a promising strategy for cancer therapy

  • Bioorg Chem. 2020 Aug;101:103970. doi: 10.1016/j.bioorg.2020.103970.
Hao Hu 1,  Fei Chen 1,  Yuhong Dong 1,  Yajing Liu 2,  Ping Gong 3
Affiliations

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: lyjpharm@126.com.
  • 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: gongpinggp@126.com.
PMID: 32480172 DOI: 10.1016/j.bioorg.2020.103970
Abstract

Owing to the low efficacy and acquired resistance in clinical trials of c-Met inhibitors, based on the synergistic effects between c-Met and HDAC, novel c-Met and HDAC dual inhibitors were designed and synthesized. We introduced 2-pyrrolidinone to form the 5-atoms linker for c-Met inhibitor and hydroxamic acid as a zinc binding motif for HDAC Inhibitor. The highly active dual inhibitor 15f showed excellent and balanced activity against both c-Met (IC50 = 12.50 nM) and HDAC1 (IC50 = 26.97 nM). In those tested tumor cell lines, 15f exhibits efficient antiproliferative activity with greater potency than Vorinostat (SAHA) and Cabozantinib (XL184). However, by comparing with an equimolar mixture of SAHA and Foretinib, we did not observe the compounds showed clearly synergistic antiproliferative effect. Nevertheless, compound 15f was found to induce Apoptosis and cause cell cycle arrest in G2/M phase. This proof-of-concept study provides an efficient strategy for discovery of multitarget antitumor drugs.

Keywords

2-Pyrrolidinone; Antitumor drug; HDAC; c-Met.

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