2. Academic Validation
  3. Discovery of 2,4-pyrimidinediamine derivatives as potent dual inhibitors of ALK and HDAC

Discovery of 2,4-pyrimidinediamine derivatives as potent dual inhibitors of ALK and HDAC

  • Eur J Med Chem. 2021 Nov 15:224:113672. doi: 10.1016/j.ejmech.2021.113672.
Tao Pan 1,  Yanrong Dan 1,  Dafeng Guo 1,  Junhao Jiang 2,  Dongzhi Ran 2,  Lin Zhang 1,  Binghua Tian 1,  Jianyong Yuan 2,  Yu Yu 3,  Zongjie Gan 4
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China.
  • 2 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China; Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China.
  • 3 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China; Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: yuyu3519@163.com.
  • 4 Department of Medicinal Chemistry, College of Pharmacy, Chongqing Medical University, Chongqing 400016, PR China; Chongqing Research Center for Pharmaceutical Engineering, Chongqing Medical University, Chongqing 400016, PR China. Electronic address: gzj@cqmu.edu.cn.
PMID: 34237620 DOI: 10.1016/j.ejmech.2021.113672
Abstract

Combination of anaplastic lymphoma kinase (ALK) inhibitor with histone deacetylases (HDAC) inhibitor could exert synergistically anti-proliferative effects on ALK positive non-small cell lung Cancer (NSCLC) naïve or resistant cells. In this work, we designed and synthesized a series of 2,4-pyrimidinediamine derivatives as dual ALK and HDAC inhibitors based on pharmacophore merged strategy. Among which, compound 10f displayed the most potent and balanced inhibitory activity against ALK (IC50 = 2.1 nM) and HDAC1 (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALKL1196M (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALKG1202R (IC50 = 0.4 nM) mutants. In antiproliferative activity assay, 10f exhibited impressive activity on ALK-addicted Cancer cell lines at low micromole concentrations, which was comparable to that of Crizotinib and Ceritinib. Further flow cytometric analysis indicated that 10f could effectively induce cell death via cell Apoptosis and cell cycle arrest. Taken together, these results suggested 10f would be a promising lead compound for the ALK-positive NSCLC treatment, especially the Ceritinib- or Crizotinib-resistant NSCLC.

Keywords

2,4-Pyrimidinediamine; ALK/HDAC dual Inhibitors; NSCLC; Pharmacophore merged strategy.

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