Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix(ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cell...Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix(ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases.Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms,including protein-protein interactions,conformational changes,and trafficking.Due to their exposure on the cell surface and sensitivity to the molecular blockade,integrins have been investigated as pharmacological targets for nearly 40 years,but given the complexity of integrins and sometimes opposite characteristics,targeting integrin therapeutics has been a challenge.To date,only seven drugs targeting integrins have been successfully marketed,including abciximab,eptifibatide,tirofiban,natalizumab,vedolizumab,lifitegrast,and carotegrast.Currently,there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies,including small molecules,antibodies,synthetic mimic peptides,antibody-drug conjugates(ADCs),chimeric antigen receptor(CAR)T-cell therapy,imaging agents,etc.A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs.Herein,we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic.In addition,we further discuss the trend of drug development,how to improve the success rate of clinical trials targeting integrin therapies,and the key points for clinical research,basic research,and translational research.展开更多
Dear Editor,The integrinαvβ3 receptor is a promising target for anticancer therapy.1,2 However,there are no effective marketed treatments targetingαvβ3.One possible limitation of Arginine-Glycine-Aspartic(RGD)-mim...Dear Editor,The integrinαvβ3 receptor is a promising target for anticancer therapy.1,2 However,there are no effective marketed treatments targetingαvβ3.One possible limitation of Arginine-Glycine-Aspartic(RGD)-mimeticαvβ3 antagonists has been shown to cause partial agonism,which could induce major conformational changes that trigger paradoxical cell adhesion and angiogenesis.展开更多
Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three g...Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three glycosyl groups(GD3) and disialoganglioside with two glycosyl groups(GD2) are markedly increased in pathological conditions such as cancers and neurodegenerative diseases. GD3 and GD2 were found to play important roles in cancers by mediating cell proliferation, migration, invasion, adhesion,angiogenesis and in preventing immunosuppression of tumors. GD3 synthase(GD3S) is the regulatory enzyme of GD3 and GD2 synthesis, and is important in tumorigenesis and the development of cancers.The study of GD3S as a drug target may be of great significance for the discovery of new drugs for cancer treatment. This review will describe the gangliosides and their roles in physiological and pathological conditions; the roles of GD3 and GD2 in cancers; the expression, functions and mechanisms of GD3S,and its potential as a drug target in cancers.展开更多
The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma dr...The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C-0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration -time curve (ALC(0-i)) values ranged from 1.75 to 11.80 (mg ' h/L). J10688 lacked dose dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.展开更多
基金This research was funded by National High Level Hospital Clinical Research Funding(Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital)(Nos.2022CX11 and 2022RT01)National Key R&D Program of China(No.2020YFC2008304)National Natural Science Foundation of China(Nos.81973320 and 81903714).Thanks to Pharmacodia database for retrieving clinical trial data.
文摘Integrins are considered the main cell-adhesion transmembrane receptors that play multifaceted roles as extracellular matrix(ECM)-cytoskeletal linkers and transducers in biochemical and mechanical signals between cells and their environment in a wide range of states in health and diseases.Integrin functions are dependable on a delicate balance between active and inactive status via multiple mechanisms,including protein-protein interactions,conformational changes,and trafficking.Due to their exposure on the cell surface and sensitivity to the molecular blockade,integrins have been investigated as pharmacological targets for nearly 40 years,but given the complexity of integrins and sometimes opposite characteristics,targeting integrin therapeutics has been a challenge.To date,only seven drugs targeting integrins have been successfully marketed,including abciximab,eptifibatide,tirofiban,natalizumab,vedolizumab,lifitegrast,and carotegrast.Currently,there are approximately 90 kinds of integrin-based therapeutic drugs or imaging agents in clinical studies,including small molecules,antibodies,synthetic mimic peptides,antibody-drug conjugates(ADCs),chimeric antigen receptor(CAR)T-cell therapy,imaging agents,etc.A serious lesson from past integrin drug discovery and research efforts is that successes rely on both a deep understanding of integrin-regulatory mechanisms and unmet clinical needs.Herein,we provide a systematic and complete review of all integrin family members and integrin-mediated downstream signal transduction to highlight ongoing efforts to develop new therapies/diagnoses from bench to clinic.In addition,we further discuss the trend of drug development,how to improve the success rate of clinical trials targeting integrin therapies,and the key points for clinical research,basic research,and translational research.
基金This research was funded by National High Level Hospital Clinical Research Funding(Scientific and Technological Achievements Transformation Incubation Guidance Fund Project of Peking University First Hospital)(No.2022CX11,No.2022RT01)National Key R&D Program of China(No.2020YFC2008304)National Natural Science Foundation of China(No.81973320 and No.81903714).Thanks to Dr.Qian Wang in the State Key Laboratory of Natural and Biomimetic Drugs,Peking University for the experimental assistance of SPR.Thanks to K2 Oncology Co.Ltd.for experimental assistance with patient-derived organoids.
文摘Dear Editor,The integrinαvβ3 receptor is a promising target for anticancer therapy.1,2 However,there are no effective marketed treatments targetingαvβ3.One possible limitation of Arginine-Glycine-Aspartic(RGD)-mimeticαvβ3 antagonists has been shown to cause partial agonism,which could induce major conformational changes that trigger paradoxical cell adhesion and angiogenesis.
基金supported by National Natural Science Foundation of China (81573454)supported by Beijing Natural Science Foundation (7172142)supported by CAMS Innovation Fund for Medical Sciences (2016-I2M-3–007)
文摘Gangliosides are a class of important glycosphingolipids containing sialic acid that are widely distributed on the outer surface of cells and are abundantly distributed in brain tissue. Disialoganglioside with three glycosyl groups(GD3) and disialoganglioside with two glycosyl groups(GD2) are markedly increased in pathological conditions such as cancers and neurodegenerative diseases. GD3 and GD2 were found to play important roles in cancers by mediating cell proliferation, migration, invasion, adhesion,angiogenesis and in preventing immunosuppression of tumors. GD3 synthase(GD3S) is the regulatory enzyme of GD3 and GD2 synthesis, and is important in tumorigenesis and the development of cancers.The study of GD3S as a drug target may be of great significance for the discovery of new drugs for cancer treatment. This review will describe the gangliosides and their roles in physiological and pathological conditions; the roles of GD3 and GD2 in cancers; the expression, functions and mechanisms of GD3S,and its potential as a drug target in cancers.
基金supported by Beijing Natural Science Foundation(7152103)the National Great Science and Technology Projects(2014ZX09507003-002 and 2012ZX09301002-2013HXW-11)the International Collaboration Project(2011DFR31240)
文摘The pharmacokinetic profile of gallocatechin-7-gallate (J10688) was studied in rats after intravenous administration. Male and female Sprague-Dawley (SD) rats received 1, 3, and 10 mg/kg (i.v.) of J10688 and plasma drug concentrations were determined by a high performance liquid chromatography-mass spectrometry (LC-MS) method. The pharmacokinetic software Data Analysis System (Version 3.0) was used to calculate the pharmacokinetic parameters. For different i.v. doses of J10688, the mean peak plasma concentration (C-0) values ranged from 11.26 to 50.82 mg/L, and mean area under the concentration -time curve (ALC(0-i)) values ranged from 1.75 to 11.80 (mg ' h/L). J10688 lacked dose dependent pharmacokinetic properties within doses between 1 and 10 mg/kg, based on the power model. The method developed in this study was sensitive, precise, and stable. The pharmacokinetic properties of J10688 in SD rats were shown to have rapid distribution and clearance values. These pharmacokinetic results may contribute to an improved understanding of the pharmacological actions of J10688. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.
