State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China; Beijing Key Laboratory of Active Substances Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Bioorg Med Chem. 2021 Jan 1;29:115890. doi: 10.1016/j.bmc.2020.115890. Epub 2020 Nov 25.
As abnormal PI3K signaling is a feature of many types of cancer, the development of orally active PI3K inhibitors is of great significance for targeted cancer therapy. Through integrating strategies of reducing aromatic character/increasing the fraction of sp carbons together with scaffold hopping, we designed and synthesized two new series of thieno[2,3-d]pyrimidine and thiazolo[5,4-d]pyrimidine derivatives for use as PI3K inhibitors. Our structure-activity relationship studies led to the identification of thieno[2,3-d]pyrimidine 6a and thiazolo[5,4-d]pyrimidine 7a, which exhibited remarkable nanomolar PI3K potency, good antiproliferative activity, favorable pharmacokinetic properties and significant in vivo anti-cancer efficacy. Notably, thiazolo[5,4-d]pyrimidine 7a had better anti-cancer activity than thieno[2,3-d]pyrimidine 6a and is worthy of further pre-clinical evaluation for its use in cancer treatment.
由于异常的 PI3K 信号是许多类型癌症的特征，因此开发口服活性的 PI3K 抑制剂对于靶向癌症治疗具有重要意义。通过整合降低芳香性/增加 sp 碳原子分数的策略以及支架跳跃，我们设计并合成了两个新的噻吩并[2,3-d]嘧啶和噻唑并[5,4-d]嘧啶衍生物系列，用作 PI3K 抑制剂。我们的构效关系研究确定了噻吩并[2,3-d]嘧啶 6a 和噻唑并[5,4-d]嘧啶 7a，它们表现出显著的纳摩尔级的 PI3K 效力、良好的抗增殖活性、良好的药代动力学特性和显著的体内抗癌疗效。值得注意的是，噻唑并[5,4-d]嘧啶 7a 比噻吩并[2,3-d]嘧啶 6a 具有更好的抗癌活性，值得进一步进行临床前评估，以用于癌症治疗。
