School of Pharmacy, Anhui Medical University, Hefei, 230032, PR China.
Department of Orthopedics, The Second Affiliated Hospital of Anhui Medical University, Hefei, 230601, PR China.
Eur J Med Chem. 2023 May 5;251:115214. doi: 10.1016/j.ejmech.2023.115214. Epub 2023 Feb 24.
CDK8 plays a key role in acute myeloid leukemia, colorectal cancer and other cancers. Here, a total of 54 compounds were designed and synthesized. Among them, the most potent one compound 43 (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide), a novel CDK8 Ⅰ inhibitor, showed strong inhibitory activity against CDK8 (IC = 51.9 nM), good kinase selectivity, good anti AML cell proliferation activity (molm-13 GC = 1.57 ± 0.59 μM) and low toxicity in vivo (acute toxicity: 2000 mg/kg). Further mechanistic studies revealed that this compound could target CDK8 and then phosphorylate STAT-1 and STAT-5 thereby inhibiting of AML cell proliferation. In addition, compound 43 showed relatively good bioavailability (F = 28.00%) and could inhibit the growth of AML tumors in a dose-dependent manner in vivo. This study facilitates the further development of more potent CDK8 inhibitors for the treatment of the AML.
CDK8 在急性髓系白血病、结直肠癌和其他癌症中发挥着关键作用。在这里，我们共设计并合成了 54 种化合物。其中，最有效的化合物 43（3-(1H-吡咯并[2,3-b]吡啶-5-基)苯甲酰胺），一种新型的 CDK8 Ⅰ抑制剂，对 CDK8 表现出强烈的抑制活性（IC = 51.9 nM），具有良好的激酶选择性、良好的抗 AML 细胞增殖活性（molm-13 GC = 1.57 ± 0.59 μM）和低体内毒性（急性毒性：2000 mg/kg）。进一步的机制研究表明，该化合物可以靶向 CDK8，然后磷酸化 STAT-1 和 STAT-5，从而抑制 AML 细胞增殖。此外，化合物 43 表现出相对较好的生物利用度（F = 28.00%），并能够在体内以剂量依赖的方式抑制 AML 肿瘤的生长。这项研究为开发更有效的 CDK8 抑制剂治疗 AML 提供了便利。
