2. Academic Validation
  3. Discovery of benzamide-based PI3K/HDAC dual inhibitors with marked pro-apoptosis activity in lymphoma cells

Discovery of benzamide-based PI3K/HDAC dual inhibitors with marked pro-apoptosis activity in lymphoma cells

  • Eur J Med Chem. 2023 Dec 15:262:115915. doi: 10.1016/j.ejmech.2023.115915.
Jingjing Deng 1,  Baogeng Hou 2,  Xiaohan Hou 2,  Yuxin Chen 2,  Tao Zhang 3,  Hua Chen 3,  Yuanze Wang 3,  Xiaoyang Li 4
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; CAS Key Laboratory of Tropical Marine BioResources and Ecology, Guangdong Key Laboratory of Marine Materia Medica, RNAM Center for Marine Microbiology, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, 510301, China.
  • 2 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China.
  • 3 Bioland Laboratory (Guangzhou Regenerative Medicine and Health-Guangdong Laboratory), Guangzhou, 510530, China.
  • 4 Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, China; Center for Targeted Protein Degradation and Drug Discovery, Ocean University of China, Qingdao, Shandong, 266003, China. Electronic address: lixiaoyang@ouc.edu.cn.
PMID: 37948955 DOI: 10.1016/j.ejmech.2023.115915
Abstract

Inhibition of PI3K and histone deacetylase (HDAC) activity simultaneously using a single molecule appears to be a promising approach for Cancer treatment. Current PI3K/HDAC dual inhibitors commonly use hydroxamate moiety as zinc binding group, which lack HDAC isoform selectivity and have potential genotoxicity. In this study, a novel series of benzamide-based PI3K/HDAC dual inhibitors were rationally designed and synthesized. Representative compound PH14 showed potent inhibitory activity toward PI3Kα and HDAC3, with IC50 values of 20.3 nM and 24.5 nM, respectively. This was further supported by the blockage of Akt phosphorylation and an increase in acetylated histone H3 levels in Western blot study. The advantage of simultaneously targeting PI3Kα and HDAC is not only reflected in the significant antiproliferative activity, but also in its ability to promote the Apoptosis in Jeko-1 cells. Moreover, PH14 had weak inhibitory effects on CYP450 Enzymes and hERG. In the pharmacokinetic study, the administration of 1 mg/kg of PH14 the administration of 1 mg/kg of PH14 resulted in a t1/2 of 10 h and an AUC (0-∞) of 2772 h ng/mL. Our study may provide ideas for the further development of novel HDAC/PI3K dual inhibitors.

Keywords

Anti-Cancer; Dual inhibitor; HDAC; PI3K; Rational drug design.

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