PARP1和CDK2在癌症发生发展中起关键作用,二者过度活化与多种肿瘤相关,同时抑制二者活性可能为乳腺癌治疗提供有效策略。本文以PARP1抑制剂Olaparib和CDK抑制剂Ribociclib为基础,通过分子对接分析选择分子尾部游离基团作为改造位点,设...PARP1和CDK2在癌症发生发展中起关键作用,二者过度活化与多种肿瘤相关,同时抑制二者活性可能为乳腺癌治疗提供有效策略。本文以PARP1抑制剂Olaparib和CDK抑制剂Ribociclib为基础,通过分子对接分析选择分子尾部游离基团作为改造位点,设计合成了5个具有全新结构的PARP-CDK双靶点抑制剂。利用核磁共振氢谱对其结构进行表征,通过测试酶抑制活性和体外抗细胞增殖活性进行生物活性评价。结果显示,双杂环链接化合物活性优于单杂环化合物,其中链接链为3,9-二氮杂螺[5.5]十一烷的化合物12c对PARP1与CDK2显示出良好的抗肿瘤效果。本研究为开发更多PARP1双靶点抑制剂奠定了重要基础。The proteins PARP1 and CDK2 are pivotal in the progression of cancer, with their excessive activation being implicated in a wide range of tumors. Targeting and simultaneously inhibiting the activities of both PARP1 and CDK2 may hold promise as a highly effective therapeutic strategy for the treatment of breast cancer. In this paper, five PARP-CDK dual-target inhibitors with a novel structure were designed and synthesized based on the PARP1 inhibitor Olaparib and the CDK inhibitor Ribociclib. The molecular docking analysis was used to select the free groups at the molecular tail as the modification sites. The structures of the inhibitors were characterized by nuclear magnetic resonance spectroscopy, and their biological activities were evaluated by testing the enzyme inhibitory activity and in vitro anti-cell proliferation activity. The results showed that the activity of the compounds with double heterocyclic linkers was better than that of the single heterocyclic compounds, and the compound 12c with a 3,9-diazaspiro [5.5] undecane linker exhibited good antitumor effects against both PARP1 and CDK2. This study lays an important foundation for the development of more PARP1 dual-target inhibitors.展开更多
Poly(ADP-ribosyl)ation(PARylation)is a posttranslational modification reversibly catalyzed by poly(ADP-ribose)polymerases(PARPs)and poly(ADP-ribose)glycohydrolases(PARGs)and plays a key role in multi-ple cellular proc...Poly(ADP-ribosyl)ation(PARylation)is a posttranslational modification reversibly catalyzed by poly(ADP-ribose)polymerases(PARPs)and poly(ADP-ribose)glycohydrolases(PARGs)and plays a key role in multi-ple cellular processes.The molecular mechanisms by which PARylation regulates innate immunity remain largely unknown in eukaryotes.Here we show that Arabidopsis UBC13A and UBC13B,the major drivers of lysine 63(K63)-linked polyubiquitination,directly interact with PARPs/PARGs.Activation of pathogen-associated molecular pattern(PAMP)-triggered immunity promotes these interactions and enhances PARylation of UBC13.Both parp1 parp2 and ubc13a ubc13b mutants are compromised in immune responses with increased accumulation of total pathogenesis-related(PR)proteins but decreased accu-mulation of secreted PR proteins.Protein disulfide-isomerases(PDIs),essential components of endo-plasmic reticulum quality control(ERQC)that ensure proper folding and maturation of proteins destined for secretion,complex with PARPs/PARGs and are PARylated upon PAMP perception.Significantly,PARylation of UBC13 regulates K63-linked ubiquitination of PDIs,which may further promote their disulfide isomerase activities for correct protein folding and subsequent secretion.Taken together,these results indicate that plant immunity is coordinately regulated by PARylation and K63-linked ubiquitination.展开更多
文摘PARP1和CDK2在癌症发生发展中起关键作用,二者过度活化与多种肿瘤相关,同时抑制二者活性可能为乳腺癌治疗提供有效策略。本文以PARP1抑制剂Olaparib和CDK抑制剂Ribociclib为基础,通过分子对接分析选择分子尾部游离基团作为改造位点,设计合成了5个具有全新结构的PARP-CDK双靶点抑制剂。利用核磁共振氢谱对其结构进行表征,通过测试酶抑制活性和体外抗细胞增殖活性进行生物活性评价。结果显示,双杂环链接化合物活性优于单杂环化合物,其中链接链为3,9-二氮杂螺[5.5]十一烷的化合物12c对PARP1与CDK2显示出良好的抗肿瘤效果。本研究为开发更多PARP1双靶点抑制剂奠定了重要基础。The proteins PARP1 and CDK2 are pivotal in the progression of cancer, with their excessive activation being implicated in a wide range of tumors. Targeting and simultaneously inhibiting the activities of both PARP1 and CDK2 may hold promise as a highly effective therapeutic strategy for the treatment of breast cancer. In this paper, five PARP-CDK dual-target inhibitors with a novel structure were designed and synthesized based on the PARP1 inhibitor Olaparib and the CDK inhibitor Ribociclib. The molecular docking analysis was used to select the free groups at the molecular tail as the modification sites. The structures of the inhibitors were characterized by nuclear magnetic resonance spectroscopy, and their biological activities were evaluated by testing the enzyme inhibitory activity and in vitro anti-cell proliferation activity. The results showed that the activity of the compounds with double heterocyclic linkers was better than that of the single heterocyclic compounds, and the compound 12c with a 3,9-diazaspiro [5.5] undecane linker exhibited good antitumor effects against both PARP1 and CDK2. This study lays an important foundation for the development of more PARP1 dual-target inhibitors.
基金supported by a start-up fund from Texas A&M AgriLife Research to J.S.a grant from the National Science Foundation(IOS-1951094)to P.H.and J.S.
文摘Poly(ADP-ribosyl)ation(PARylation)is a posttranslational modification reversibly catalyzed by poly(ADP-ribose)polymerases(PARPs)and poly(ADP-ribose)glycohydrolases(PARGs)and plays a key role in multi-ple cellular processes.The molecular mechanisms by which PARylation regulates innate immunity remain largely unknown in eukaryotes.Here we show that Arabidopsis UBC13A and UBC13B,the major drivers of lysine 63(K63)-linked polyubiquitination,directly interact with PARPs/PARGs.Activation of pathogen-associated molecular pattern(PAMP)-triggered immunity promotes these interactions and enhances PARylation of UBC13.Both parp1 parp2 and ubc13a ubc13b mutants are compromised in immune responses with increased accumulation of total pathogenesis-related(PR)proteins but decreased accu-mulation of secreted PR proteins.Protein disulfide-isomerases(PDIs),essential components of endo-plasmic reticulum quality control(ERQC)that ensure proper folding and maturation of proteins destined for secretion,complex with PARPs/PARGs and are PARylated upon PAMP perception.Significantly,PARylation of UBC13 regulates K63-linked ubiquitination of PDIs,which may further promote their disulfide isomerase activities for correct protein folding and subsequent secretion.Taken together,these results indicate that plant immunity is coordinately regulated by PARylation and K63-linked ubiquitination.
