Department of Medicinal Chemistry, Institute for Therapeutics Discovery and Development, College of Pharmacy, University of Minnesota, 717 Delaware Street, SE, Minneapolis, MN, 55455, USA.
Department of Molecular and Integrative Physiology, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA.
Eur J Med Chem. 2021 Mar 15;214:113232. doi: 10.1016/j.ejmech.2021.113232. Epub 2021 Jan 31.
Over 50 tetrahydroindazoles were synthesized after 7-bromo-3,6,6-trimethyl-1-(pyridin-2-yl)-5,6,7,7a-tetrahydro-1H-indazol-4(3aH)-one (3) was identified as a hit compound in a high throughput screen for inhibition of CDK2 in complex with cyclin A. The activity of the most promising analogues was evaluated by inhibition of CDK2 enzyme complexes with various cyclins. Analogues 53 and 59 showed 3-fold better binding affinity for CDK2 and 2- to 10-fold improved inhibitory activity against CDK2/cyclin A1, E, and O compared to screening hit 3. The data from the enzyme and binding assays indicate that the binding of the analogues to a CDK2/cyclin complex is favored over binding to free CDK2. Computational analysis was used to predict a potential binding site at the CDK2/cyclin E1 interface.
超过 50 种四氢吲哚类化合物被合成，此前在高内涵筛选中鉴定出 7-溴-3,6,6-三甲基-1-(2-吡啶基)-5,6,7,7a-四氢-1H-吲哚-4(3aH)-酮（3）是抑制 CDK2 与 cyclin A 形成复合物的有效化合物。最有前途的类似物的活性通过抑制不同 cyclin 的 CDK2 酶复合物进行评估。与筛选出的 3 相比，类似物 53 和 59 对 CDK2 的结合亲和力提高了 3 倍，对 CDK2/cyclin A1、E 和 O 的抑制活性提高了 2 到 10 倍。来自酶和结合测定的数据表明，类似物与 CDK2/cyclin 复合物的结合优于与游离 CDK2 的结合。计算分析用于预测 CDK2/cyclin E1 界面的潜在结合位点。
