Department of Integrated Traditional Chinese and Western Medicine Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang 110042, China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Bioorg Med Chem. 2021 May 1;37:116108. doi: 10.1016/j.bmc.2021.116108. Epub 2021 Mar 14.
To address drug resistance caused by ALK kinase mutations, a series of novel 2,4-diarylaminopyrimidine (DAAP) analogues were designed by incorporating 1H-benzo[d]imidazol motif onto the maternal framework. All compounds were efficiently synthesized and antiproliferative activities against Karpas299, H2228 and A549 cell lines were evaluated by MTT assay. Delightly, the most promising derivative H-11 was detected with IC values of 0.016 μM and 0.099 μM against ALK- positive Karpas299 and H2228 cells. Meanwhile, H-11 displayed encouraging enzymatic inhibitory potency with IC values of 2.7 nM, 3.8 nM and 5.7 nM toward ALK, ALK and ALK, respectively. Ultimately, the binding modes of optimal H-11 with ALK wild-type and mutants were ideally established which further confirmed the structural basis in accordance with the SARs analysis.
为了解决 ALK 激酶突变引起的耐药性问题，我们通过在母体框架上引入 1H-苯并[d]咪唑基序，设计了一系列新型的 2,4-二芳基氨基嘧啶（DAAP）类似物。所有化合物均通过 MTT 测定法进行了高效合成，并评估了它们对 Karpas299、H2228 和 A549 细胞系的抗增殖活性。令人高兴的是，最有前途的衍生物 H-11 对阳性的 Karpas299 和 H2228 细胞的 IC 值分别为 0.016 μM 和 0.099 μM。同时，H-11 对 ALK、ALK 和 ALK 的 IC 值分别为 2.7 nM、3.8 nM 和 5.7 nM，显示出令人鼓舞的酶抑制效力。最终，我们理想地建立了最佳 H-11 与 ALK 野生型和突变体的结合模式，这进一步证实了结构基础与 SARs 分析一致。
