Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China.
Central Research Institute, Shanghai Pharmaceuticals Holding Co., Ltd., Building 5, No. 898 Halei Road, Zhangjiang Hi-tech Park, Pudong New Area, Shanghai, 201203, PR China.
Eur J Med Chem. 2020 May 1;193:112239. doi: 10.1016/j.ejmech.2020.112239. Epub 2020 Mar 16.
CDK4/6 has been identified as an attractive therapeutic target for treatment of cancer. For unmet clinical needs, a novel class of imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives, which had distinctive triheteroaryl structure, had been discovered as CDK4/6 inhibitors. The compounds 10b and 10c, displayed the low nanomolar range activities on CDK4/6, desirable antiproliferative activities, excellent metabolic properties, and acceptable pharmacokinetic characters. In Colo-205 and U87MG xenograft models, compounds 10b and 10c also showed significant tumor growth inhibitions with controllable toxicities. All data confirmed that imidazo [1',2':1,6]pyrido [2,3-d]pyrimidin derivatives 10b and 10c could be promising drug candidates for cancer therapy.
CDK4/6 已被确定为癌症治疗的有吸引力的治疗靶点。为了满足未满足的临床需求，已经发现了一类新型的咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶衍生物，它们具有独特的三杂芳基结构，作为 CDK4/6 抑制剂。化合物 10b 和 10c 在 CDK4/6 上表现出低纳摩尔范围的活性、理想的抗增殖活性、优异的代谢特性和可接受的药代动力学特征。在 Colo-205 和 U87MG 异种移植模型中，化合物 10b 和 10c 也表现出显著的肿瘤生长抑制作用，且毒性可控。所有数据证实，咪唑并[1',2':1,6]吡啶并[2,3-d]嘧啶衍生物 10b 和 10c 可能是癌症治疗有前途的候选药物。
