Infectious Diseases Therapeutic Research Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea; Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea.
Department of Medicine, Yonsei University College of Medicine, Seoul 03722, Republic of Korea; Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
Bioorg Med Chem Lett. 2021 Sep 1;47:128226. doi: 10.1016/j.bmcl.2021.128226. Epub 2021 Jun 26.
As DYRK1A and 1B inhibitors, 1H-pyrazolo[3,4-b]pyridine derivatives were synthesized. Mostly, 3-aryl-5-arylamino compounds (6) and 3,5-diaryl compounds (8 and 9) were prepared and especially, 3,5-diaryl compound 8 and 9 showed excellent DYRK1B inhibitory enzymatic activities with IC Values of 3-287 nM. Among them, 3-(4-hydroxyphenyl), 5-(3,4-dihydroxyphenyl)-1H-pyrazolo[3,4-b]pyridine (8h) exhibited the highest inhibitory enzymatic activity (IC = 3 nM) and cell proliferation inhibitory activity (IC = 1.6 µM) towards HCT116 colon cancer cells. Also compound 8h has excellent inhibitory activities in patient-derived colon cancer organoids model as well as in 3D spheroid assay model of SW480 and SW620. The docking study supported that we confirmed that compound 8h binds to DYRK1B through various hydrogen bonding interactions and hydrophobic interactions.
作为 DYRK1A 和 1B 的抑制剂，合成了 1H-吡唑并[3,4-b]吡啶衍生物。主要制备了 3-芳基-5-芳基氨基化合物（6）和 3,5-二芳基化合物（8 和 9），特别是 3,5-二芳基化合物 8 和 9 对 DYRK1B 具有优异的酶抑制活性，IC 值为 3-287 nM。其中，3-(4-羟基苯基），5-(3,4-二羟基苯基）-1H-吡唑并[3,4-b]吡啶（8h）表现出最高的酶抑制活性（IC = 3 nM）和对 HCT116 结肠癌细胞的增殖抑制活性（IC = 1.6 μM）。化合物 8h 在源自患者的结肠癌细胞类器官模型以及 SW480 和 SW620 的 3D 球体测定模型中也具有出色的抑制活性。对接研究支持我们的结论，即化合物 8h 通过各种氢键相互作用和疏水相互作用与 DYRK1B 结合。
