The inhibition of cyclin-dependent kinases(CDKs)is considered a promising strategy for cancer treatment due to their role in cell cycle regulation.However,CDK inhibitors with no selectivity among CDK families have not...The inhibition of cyclin-dependent kinases(CDKs)is considered a promising strategy for cancer treatment due to their role in cell cycle regulation.However,CDK inhibitors with no selectivity among CDK families have not been approved.A CDK inhibitor with high selectivity for CDK4/6 exhibited significant treatment effects on breast cancer and has become a heavy bomb on the market.Subsequently,resistance gradually decreased the efficacy of selective CDK4/6 inhibitors in breast cancer treatment.In this review,we first introduce the development of selective CDK4/6 inhibitors and then explain the role of CDK2 activation in inducing resistance to CDK4/6 inhibitors.Moreover,we focused on the development of CDK2/4/6 inhibitors and selective CDK2 inhibitors,which will aid in the discovery of novel CDK inhibitors targeting the cell cycle in the future.展开更多
Hematologic malignancies,including leukemia,lymphoma,and multiple myeloma,are hazardous diseases characterized by the uncontrolled proliferation of cancer cells.Dysregulated cell cycle resulting from genetic and epige...Hematologic malignancies,including leukemia,lymphoma,and multiple myeloma,are hazardous diseases characterized by the uncontrolled proliferation of cancer cells.Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events.Importantly,cyclin-dependent kinases(CDKs),complexed with their functional partner cyclins,play dominating roles in cell cycle control.Yet,efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes.Recently,mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase(WEE1)to modulate CDK activity,and correspondingly,a variety of therapeutic inhibitors have been developed to achieve clinical benefits.Thus,WEE1 may become a promising target to modulate the abnormal cell cycle.However,its function in hematologic diseases remains poorly elucidated.In this review,focusing on hematologic malignancies,we describe the biological structure of WEE1,emphasize the latest reported function of WEE1 in the carcinogenesis,progression,as well as prognosis,and finally summarize the therapeutic strategies by targeting WEE1.展开更多
基金supported by the National Key R&D Program of China(No.2023YFC2706303)the National Natural Science Foundation of China(Nos.82373738 and 82304293)Natural Science Foundation of Jiangsu Province(Nos.SBK2024090146 and BK20221040).
文摘The inhibition of cyclin-dependent kinases(CDKs)is considered a promising strategy for cancer treatment due to their role in cell cycle regulation.However,CDK inhibitors with no selectivity among CDK families have not been approved.A CDK inhibitor with high selectivity for CDK4/6 exhibited significant treatment effects on breast cancer and has become a heavy bomb on the market.Subsequently,resistance gradually decreased the efficacy of selective CDK4/6 inhibitors in breast cancer treatment.In this review,we first introduce the development of selective CDK4/6 inhibitors and then explain the role of CDK2 activation in inducing resistance to CDK4/6 inhibitors.Moreover,we focused on the development of CDK2/4/6 inhibitors and selective CDK2 inhibitors,which will aid in the discovery of novel CDK inhibitors targeting the cell cycle in the future.
基金supported by grants from the National Natural Science Foundation of China(No.81920108004,82270127,82203880)the Hunan Provincial Natural Science Foundation of China(No.2023JJ30928,2024JJ3037)+2 种基金the Changsha Municipal Natural Sci-Science Foundation(No.kq2208382)the Fellowship of the China Postdoctoral Science Foundation(No.2023T160740)the Hunan Province Clinical Medical Technology Innovation Guidance Project(No.2021SK50917,2023SK4056)。
文摘Hematologic malignancies,including leukemia,lymphoma,and multiple myeloma,are hazardous diseases characterized by the uncontrolled proliferation of cancer cells.Dysregulated cell cycle resulting from genetic and epigenetic abnormalities constitutes one of the central events.Importantly,cyclin-dependent kinases(CDKs),complexed with their functional partner cyclins,play dominating roles in cell cycle control.Yet,efforts in translating CDK inhibitors into clinical benefits have demonstrated disappointing outcomes.Recently,mounting evidence highlights the emerging significance of WEE1 G2 checkpoint kinase(WEE1)to modulate CDK activity,and correspondingly,a variety of therapeutic inhibitors have been developed to achieve clinical benefits.Thus,WEE1 may become a promising target to modulate the abnormal cell cycle.However,its function in hematologic diseases remains poorly elucidated.In this review,focusing on hematologic malignancies,we describe the biological structure of WEE1,emphasize the latest reported function of WEE1 in the carcinogenesis,progression,as well as prognosis,and finally summarize the therapeutic strategies by targeting WEE1.
