Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
Bioorg Med Chem. 2021 Oct 1;47:116396. doi: 10.1016/j.bmc.2021.116396. Epub 2021 Sep 8.
In order to explore novel TRK and ALK dual inhibitors, a series of 2-phenylamino-4-prolylpyrimidine derivatives were designed, synthesized and evaluated for their in vitro cytotoxicity and enzymatic activities. Delightfully, most compounds were detected moderated to excellent activities in cellular assay. Among them, compound 21 exhibited encouraging cytotoxicity on KM12, H2228 and KARPAS299 cells with IC values of 0.86, 0.141 and 0.072 μM. Meanwhile, the performances of 21 in the enzymatic assays were in good accordance with anti-proliferative activity with IC values of 2.2, 9.3 and 38 nM towards TRKA, ALK and ALK, respectively. Compared with Entrectinib, compound 21 not only ensured the inhibitory activity on TRKA, but also improved the affinity with ALK and ALK to a certain extent. Ultimately, the binding model of 21 with TRKA and ALK were ideally established through molecular docking, which further confirmed the SARs analysis.
为了探索新型 TRK 和 ALK 双重抑制剂，设计、合成了一系列 2-苯氨基-4-脯氨嘧啶衍生物，并对其体外细胞毒性和酶活性进行了评价。令人高兴的是，大多数化合物在细胞测定中均显示出中等至优异的活性。其中，化合物 21 对 KM12、H2228 和 KARPAS299 细胞表现出令人鼓舞的细胞毒性，IC50 值分别为 0.86、0.141 和 0.072 μM。同时，化合物 21 在酶活性测定中的表现与抗增殖活性一致，对 TRKA、ALK 和 ALK 的 IC50 值分别为 2.2、9.3 和 38 nM。与恩曲替尼相比，化合物 21 不仅保证了对 TRKA 的抑制活性，而且在一定程度上提高了与 ALK 和 ALK 的亲和力。最终，通过分子对接理想地建立了 21 与 TRKA 和 ALK 的结合模型，进一步证实了 SARs 分析。
