Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediat...Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.展开更多
目的为新型程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)小分子抑制剂的研发提供参考。方法检索PubMed、Embase、Web of Science、ClinicalTrails.gov、中国知网、万方数据库2010年至2023年的PD-1/PD-L1小分子抑制剂相关文献,汇总...目的为新型程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)小分子抑制剂的研发提供参考。方法检索PubMed、Embase、Web of Science、ClinicalTrails.gov、中国知网、万方数据库2010年至2023年的PD-1/PD-L1小分子抑制剂相关文献,汇总并分析该类制剂的研发现状。结果与结论有成药潜力的PD-1/PD-L1小分子抑制剂共20种,包括CA-170(口服小分子抑制剂)、INCB086550(特异性PD-L1抑制剂)、DPPA-1(特异性抑制PD-1/PD-L1相互作用的多肽类拮抗剂)等,其中前两者已进入临床试验阶段。PD-1/PD-L1小分子抑制剂具有特异性抑制免疫检查点的药效作用特点,以及可口服、稳定性较好、膜通透性较高等优点,但其治疗效果仍需临床试验验证。展开更多
Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are ...Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug treatment.Among the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural products.The unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and technologies.This review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule drugs.The application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.展开更多
背景与目的小分子靶向药物发生耐药的机制及寻找克服耐药的手段是目前提高临床疗效需要迫切解决的问题。本研究探讨采用不同方法建立对Crizotinib耐药的非小细胞肺癌NCI-H2228/Crizotinib细胞株的可行性及鉴定分析,为深入研究Crizotini...背景与目的小分子靶向药物发生耐药的机制及寻找克服耐药的手段是目前提高临床疗效需要迫切解决的问题。本研究探讨采用不同方法建立对Crizotinib耐药的非小细胞肺癌NCI-H2228/Crizotinib细胞株的可行性及鉴定分析,为深入研究Crizotinib耐药发生的机制并寻找克服耐药的手段提供实验基础和理论依据。方法采用逐步增加药物浓度和化学诱变剂处理NCI-H2228细胞,诱导细胞对Crizotinib耐药。MTT法检测亲本细胞和耐药细胞的50%抑制浓度(50%inhibitory concentration,IC50)和群体倍增时间。RT-PCR和Western blot实验检测棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶(echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase,EML4-ALK)基因表达。对耐药细胞和亲本细胞的EML4-ALK基因全长测序并对比分析发生耐药的机制。结果逐步增加药物浓度的方法耗时过长,细胞恢复生长缓慢,不能有效诱导NCI-H2228细胞对Crizotinib耐药;化学诱变剂ENU可以在短时间内诱导NCI-H2228细胞对Crizotinib耐药[IC50=(3.810±1.100)μmol/L,P=0.002,9,vs亲本细胞]。耐药细胞EML4-ALK基因发生点突变的频率高于亲本细胞。结论化学诱变剂诱导细胞耐药操作简便,可有效缩短实验流程,为深入研究耐药发生机制,寻找克服靶向药物耐药的手段提供了前期技术方法和实验依据。展开更多
文摘Abnormal expression or mutations in Ras proteins has been found in up to 30% of cancer cell types, making them excellent protein models to probe structure-function relationships of cell-signaling processes that mediate cell transformtion. Yet, there has been very little development of therapies to help tackle Ras-related diseased states. The development of small molecules to target Ras proteins to potentially inhibit abnormal Ras-stimulated cell signaling has been conceptualized and some progress has been made over the last 16 or so years. Here, we briefly review studies characterizing Ras protein-small molecule interactions to show the importance and potential that these small molecules may have for Ras-related drug discovery. We summarize recent results, highlighting small molecules that can be directly targeted to Ras using Structure-Based Drug Design (SBDD) and Fragment-Based Lead Discovery (FBLD) methods. The inactivation of Ras oncogenic signaling in vitro by small molecules is currently an attractive hurdle to try to and leap over in order to attack the oncogenic state. In this regard, important features of previously characterized properties of small molecule Ras targets, as well as a current understanding of conformational and dynamics changes seen for Ras-related mutants, relative to wild type, must be taken into account as newer small molecule design strategies towards Ras are developed.
文摘目的为新型程序性死亡受体-1(PD-1)/程序性死亡配体-1(PD-L1)小分子抑制剂的研发提供参考。方法检索PubMed、Embase、Web of Science、ClinicalTrails.gov、中国知网、万方数据库2010年至2023年的PD-1/PD-L1小分子抑制剂相关文献,汇总并分析该类制剂的研发现状。结果与结论有成药潜力的PD-1/PD-L1小分子抑制剂共20种,包括CA-170(口服小分子抑制剂)、INCB086550(特异性PD-L1抑制剂)、DPPA-1(特异性抑制PD-1/PD-L1相互作用的多肽类拮抗剂)等,其中前两者已进入临床试验阶段。PD-1/PD-L1小分子抑制剂具有特异性抑制免疫检查点的药效作用特点,以及可口服、稳定性较好、膜通透性较高等优点,但其治疗效果仍需临床试验验证。
基金supported by grants from the National Natural Science Foundation of China(No.31870946)the Funding of Double First-rate discipline construction(No.CPU2018GF07)+1 种基金the Priority Academic Program Development of Jiangsu Higher Education Institutionsthe Open Project Program of MOE Key Laboratory of Drug Quality Control and Pharmacovigilance(No.DQCP20/21MS01).
文摘Target discovery,involving target identification and validation,is the prerequisite for drug discovery and screening.Novel methodologies and technologies for the precise discovery and confirmation of drug targets are powerful tools in understanding the disease,looking for a drug and elucidating the mechanism of drug treatment.Among the common target identification and confirmation methods,the modified method is time-consuming and laborious,which may reduce or change the activity of natural products.The unmodified methods developed in recent years without chemical modification have gradually become an important means of studying drug targets.A wide range of unmodified approaches have been reported,introducing and analyzing the recent emerging methodologies and technologies.This review highlights the advantages and limitations of these methods for the application of drug target discovery and presents an overview of their contributions to the target discovery of small molecule drugs.The application and future development trends of methodologies in target discovery are also prospected to provide a reference for drug target research.
文摘背景与目的小分子靶向药物发生耐药的机制及寻找克服耐药的手段是目前提高临床疗效需要迫切解决的问题。本研究探讨采用不同方法建立对Crizotinib耐药的非小细胞肺癌NCI-H2228/Crizotinib细胞株的可行性及鉴定分析,为深入研究Crizotinib耐药发生的机制并寻找克服耐药的手段提供实验基础和理论依据。方法采用逐步增加药物浓度和化学诱变剂处理NCI-H2228细胞,诱导细胞对Crizotinib耐药。MTT法检测亲本细胞和耐药细胞的50%抑制浓度(50%inhibitory concentration,IC50)和群体倍增时间。RT-PCR和Western blot实验检测棘皮动物微管相关蛋白样4-间变性淋巴瘤激酶(echinoderm microtubule-associated protein like 4-anaplastic lymphoma kinase,EML4-ALK)基因表达。对耐药细胞和亲本细胞的EML4-ALK基因全长测序并对比分析发生耐药的机制。结果逐步增加药物浓度的方法耗时过长,细胞恢复生长缓慢,不能有效诱导NCI-H2228细胞对Crizotinib耐药;化学诱变剂ENU可以在短时间内诱导NCI-H2228细胞对Crizotinib耐药[IC50=(3.810±1.100)μmol/L,P=0.002,9,vs亲本细胞]。耐药细胞EML4-ALK基因发生点突变的频率高于亲本细胞。结论化学诱变剂诱导细胞耐药操作简便,可有效缩短实验流程,为深入研究耐药发生机制,寻找克服靶向药物耐药的手段提供了前期技术方法和实验依据。
