Idiopathic pulmonary fibrosis(IPF)is a chronic fatal lung disease characterized by destruction of lung parenchyma and deposition of extracellular matrix in interstitial and alveolar spaces.But known drugs for IPF are far from meeting clinical demands,validation of drug targets against pulmonary fibrosis is in urgent demand.Tyrosine kinase receptor DDRs has been considered as a potential therapeutic target for pulmonary fibrosis due to its pathological collagen binding property and the roles in regulating extracellular matrix remodeling.In this study we designed and synthesized a new indazole derivative XBU-13,and identified XBU-13 as a highly specific and potent DDRs inhibitor with anti-inflammation and anti-fibrosis activities.We first demonstrated that DDR1/2 was highly expressed in the lung tissues of IPF patients.Then we showed that XBU-13 potently inhibited DDR1 and DDR2 kinases with IC50 values of 17.18 nM and 15.13 nM,respectively.Among a panel of 34 kinases tested,XBU-13 displayed relatively high selectivity for DDRs with minimal inhibitory effect on PDGFR family and FGFR1,as well as Abi kinase that had high homology with DDRs.Extensive profiling of XBU-13 revealed that the new inhibitor had much lower toxicity than nintedanib and better pharmacokinetic properties in mice.Furthermore,pharmacodynamic evaluation conducted in bleomycin-induced pulmonary fibrosis mice showed that administration of XBU-13(30,60,90 mg·kg-1·d-1,i.g.)for 12 days significantly and dose-dependently ameliorated lung inflammation and fibrosis.Together,this study confirms that DDRs kinase is a potential target for PF,Particularly,compound XBU-13 is a highly potent and specific DDRs inhibitor,along with good pharmacokinetics profiles,and preferable in vivo efficacy,suggesting that it is a potential candidate for the treatment of PF.

Ying Dong;Bi-xi Tang;Qi Wang;Li-wei Zhou;Cong Li;Xuan Zhang;Dan-dan Sun;Xin Sun;Xue-mei Zhang;Bing Xiong;Jia Li;Hong Shi;Dan-qi Chen;Yi Zang

State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;University of Chinese Academy of Sciences,Beijing 100049,China;Department of Pharmacology,School of Pharmacy,Fudan University,Shanghai 201203,China;Department of Medicinal Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203,China;Center for Supramolecular Chemistry and Catalysis and Department of Chemistry,College of Sciences,Shanghai University,Shanghai 200444,China;Schoolof Chinese Materia Medica,Nanjing University of Chinese Medicine,Nanjing 210023,China;Schoolof Pharmacy,Henan University,Kaifeng 475004,China;Open Studio for Druggability Research of Marine Natural Products,Pilot National Laboratory for Marine Science and Technology(Qingdao),Qingdao 266237,China;School of Pharmaceutical Science and Technology,Hangzhou Institute for Advanced Study,UCAS,Hangzhou 310024,China;Department of Anesthesiology of Shanghai Pulmonary Hospital,School of medicine,Tongji University,Shanghai 200433,China

中国药理学报（英文版）

[1]Ying Dong;Bi-xi Tang;Qi Wang;Li-wei Zhou;Cong Li;Xuan Zhang;Dan-dan Sun;Xin Sun;Xue-mei Zhang;Bing Xiong;Jia Li;Hong Shi;Dan-qi Chen;Yi Zang-.Discovery of a novel DDRs kinase inhibitor XBLJ-13 for the treatment of idiopathic pulmonary fibrosis)[J].中国药理学报（英文版）,2022(07):1769-1779

DDRs,XBLJ,XBU,Abi,nintedanib

Discovery,novel,treatment,idiopathic,pulmonary,fibrosis,Idiopathic,IPF,chronic,fatal,lung,disease,characterized,by,destruction,parenchyma,deposition,extracellular,matrix,interstitial,alveolar,spaces,But,known,drugs,far,from,meeting,clinical,demands,validation,targets,against,urgent,Tyrosine,receptor,has,been,considered,potential,therapeutic,due,its,pathological,collagen,binding,property,roles,regulating,remodeling,In,this,study,designed,synthesized,new,indazole,derivative,identified,highly,specific,anti,inflammation,activities,We,first,demonstrated,that,DDR1,was,expressed,tissues,patients,Then,showed,potently,inhibited,DDR2,kinases,IC50,values,nM,respectively,Among,panel,tested,displayed,relatively,selectivity,minimal,inhibitory,effect,PDGFR,family,FGFR1,well,had,homology,Extensive,profiling,revealed,much,lower,toxicity,than,better,properties,mice,Furthermore,pharmacodynamic,evaluation,conducted,bleomycin,induced,administration,days,significantly,dose,dependently,ameliorated,Together,confirms,Particularly,compound,along,good,pharmacokinetics,profiles,preferable,vivo,efficacy,suggesting,candidate

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