2. Academic Validation
  3. Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia

Rational design and optimization of novel 4-methyl quinazoline derivatives as PI3K/HDAC dual inhibitors with benzamide as zinc binding moiety for the treatment of acute myeloid leukemia

  • Eur J Med Chem. 2024 Jan 15:264:116015. doi: 10.1016/j.ejmech.2023.116015.
Kehui Zhang 1,  Rui Huang 2,  Ming Ji 3,  Songwen Lin 1,  Fangfang Lai 3,  Deyu Wu 1,  Hua Tian 1,  Jinhui Bi 1,  Shouguo Peng 1,  Jiaqi Hu 1,  Li Sheng 4,  Yan Li 4,  Xiaoguang Chen 5,  Heng Xu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing, 100050, China.
  • 2 Tianjin Key Laboratory of Therapeutic Substance of Traditional Chinese Medicine, Tianjin, 301617, China; School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing, 100050, China.
  • 4 Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PD Study, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: [email protected].
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China; Key Laboratory of Small Molecule Immuno-Oncology Drug Discovery, Chinese Academy of Medical Sciences, Beijing, 100050, China. Electronic address: [email protected].
PMID: 38048697 DOI: 10.1016/j.ejmech.2023.116015
Abstract

Simultaneous inhibition of PI3K and HDAC has shown promise for treating various cancers, leading to discovery and development of their dual inhibitors as novel Anticancer agents. Herein, we disclose a new series of PI3K/HDAC dual inhibitors bearing a benzamide moiety as the pharmacophore of HDAC inhibition. Based on systematic structure-activity relationship study, compounds 36 and 51 featuring an alkyl and benzoyl linker respectively were identified with favorable potencies against both PI3K and HDAC. In cellular assays, compounds 36 and 51 showed significantly enhanced antiproliferative activities against various Cancer cell lines relative to single-target inhibitors. Furthermore, western blotting analysis shows compounds 36 and 51 suppressed Akt phosphorylation and increased H3 acetylation in MV4-11 cells, while flow cytometry analysis reveals both compounds dose-dependently induced cell cycle arrest and cell Apoptosis. Supported by pharmacokinetic studies, compounds 36 and 51 were subjected to the in vivo evaluation in a MV4-11 xenograft model, demonstrating significant and dose-dependent Anticancer efficacies. Overall, this work provides a promising approach for the treatment of AML by simultaneously inhibiting PI3K and HDAC with a dual inhibitor.

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