Evodiamine-Inspired Topoisomerase-Histone Deacetylase Dual Inhibitors: Novel Orally Active Antitumor Agents for Leukemia Therapy

  • J Med Chem. 2022 Mar 24;65(6):4818-4831. doi: 10.1021/acs.jmedchem.1c02026.
Shanchao Wu  1 ,  Yahui Huang  1 ,  Ting Wang  2  3 ,  Keliang Li  1 ,  Junjie Lu  1 ,  Min Huang  2  3 ,  Guoqiang Dong  1 ,  Chunquan Sheng  1
Affiliations
  • 1. Department of Medicinal Chemistry, School of Pharmacy, Second Military Medical University, 325 Guohe Road, Shanghai 200433, China.
  • 2. Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3. University of the Chinese Academy of Sciences, Beijing 100049, China.
PMID: 35238576 DOI: 10.1021/acs.jmedchem.1c02026
Abstract

On the basis of the synergism of Topoisomerase (Top) and histone deacetylase (HDAC) inhibitors in antitumor therapy, a series of novel Top/HDAC dual inhibitors were designed and synthesized by the pharmacophore fusion strategy. After systematic structure-activity relationship studies, lead compound 16j was identified to simultaneously inhibit both Top and HDAC with good potency, which showed potent antiproliferative activities with a broad spectrum. Mechanistic studies indicated that compound 16j efficiently induced Apoptosis with S cell-cycle arrest in HEL Cancer cells. It was orally active in HEL xenograft models and exhibited excellent in vivo antitumor efficacy (TGI = 68.5%; 10 mg/kg). Altogether, this work highlights the therapeutic potential of evodiamine-inspired Top/HDAC dual inhibitors and provides a valuable lead compound for the development of novel antitumor agents for leukemia therapy.

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