Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, PR China.
Bioorg Med Chem. 2020 Oct 15;28(20):115715. doi: 10.1016/j.bmc.2020.115715. Epub 2020 Aug 20.
Aiming to identify new optimization strategy effective for ALK-mutations, two series of pyrroformyl-containing 2,4-diaminopyrimidine compounds (11a-o, 12a-o) were designed, synthesized and evaluated for their anti-proliferative activities against three cancer cell lines in vitro by MTT assay. The biological evaluations on cellular assay resulted in discovery of compound 11k, which performed considerable activity with IC value of 0.034 μM against H2228 cell. Meanwhile, 11k exhibited outstanding enzymatic inhibitory potency with IC values of 1.9 nM and 3.1 nM against ALK and ALK, respectively, surpassing the reference ceritinib (IC = 2.4 nM and 7.6 nM). Ultimately, the binding mode of 11k with ALK was established to explore the SARs. Overall, 11k was considered as a promising ALK inhibitor for mutation treatment.
为了确定针对 ALK 突变的有效优化策略，设计、合成了两个系列含有吡咯甲酰基的 2,4-二氨基嘧啶类化合物（11a-o，12a-o），并通过 MTT 法评估了它们在体外对三种癌细胞系的抗增殖活性。细胞试验的生物学评价发现了化合物 11k，其对 H2228 细胞的 IC 值为 0.034 μM，表现出相当的活性。同时，11k 对 ALK 和野生型 ALK 的抑制活性分别为 1.9 nM 和 3.1 nM，优于对照药物色瑞替尼（IC = 2.4 nM 和 7.6 nM）。最后，建立了 11k 与 ALK 的结合模式，以探讨 SARs。总之，11k 被认为是一种有前途的用于突变治疗的 ALK 抑制剂。
