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
复制标题
发现 2,4-嘧啶二胺衍生物作为 ALK 和 HDAC 的有效双重抑制剂
DOI：
10.1016/j.ejmech.2021.113672
复制
发表时间：
2021-07-05
影响因子：
6.7
通讯作者：
Gan, Zongjie
中科院分区：
文献类型：
--
作者：
Pan, Tao;Dan, Yanrong;Gan, Zongjie
间变性淋巴瘤激酶（ALK）抑制剂与组蛋白脱乙酰基酶（HDAC）抑制剂联合使用可对ALK阳性非小细胞肺癌（NSCLC）初始或耐药细胞发挥协同抗增殖作用。本论文基于药效团合并策略，设计并合成了一系列2，4-嘧啶二胺衍生物作为ALK和HDAC的双重抑制剂。其中，化合物10 f分别对ALK（IC 50 = 2.1 nM）和HDACl（IC 50 = 7.9 nM）显示出最强和平衡的抑制活性。特别是，10 f对常见的克唑替尼耐药ALK（L1196 M）（IC 50 = 1.7 nM）以及Ceritinib耐药ALK（G1202 R）（IC 50 = 0.4 nM）突变体也有效。在抗增殖活性试验中，10 f在低微摩尔浓度下对ALK成瘾癌细胞系表现出令人印象深刻的活性，与克唑替尼和Ceritinib相当。进一步的流式细胞术分析表明，10 f可以有效地诱导细胞死亡，通过细胞凋亡和细胞周期阻滞。综上所述，这些结果表明10 f将是ALK阳性NSCLC治疗的有希望的先导化合物，特别是Ceritinib或克唑替尼耐药NSCLC。(C)2021 Elsevier Masson SAS。All rights reserved.
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) naive 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 HDACl (IC50 = 7.9 nM), respectively. In particular, 10f was also potent against the frequently observed Crizotinib-resistant ALK(L1196M) (IC50 = 1.7 nM) as well as the Ceritinib-resistant ALK(G1202R) (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. (C) 2021 Elsevier Masson SAS. All rights reserved.