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SBL-JP-0004:A promising dual inhibitor of jak2 and PI3KCD against gastric cancer

Oncology Research 2025年第1期33卷 235-243页

作者： HASSAN M.OTIFI Department of Pathology College of MedicineKing Khalid UniversityAbha62521Saudi Arabia

Background:Gastric cancer(GC)remains a global health burden and is often characterized by heterogeneous molecular profiles and resistance to conventional *** phosphoinositide 3-kinase and PI3K and Janus kinase(jak)signal transducer and activator of transcription(jak-STAT)pathways play pivotal roles in GC progression,making them attractive targets for therapeutic ***:This study applied a computational and molecular dynamics simulation approach to identify and characterize SBL-JP-0004 as a potential dual inhibitor of jak2 and PI3KCD *** and SNU-5 GC cells were used for in vitro ***:SBL-JP-0004 exhibited a robust binding affinity for jak2 and PI3KCD kinases,as evidenced by molecular docking scores and molecular dynamics *** interactions and Gibbs binding free energy estimates confirmed stable and favorable interactions with target ***-JP-0004 displayed an half-maximal inhibitory concentration(IC_(50))value of 118.9 nM against jak2 kinase and 200.9 nM against PI3KCD ***-JP-0004 exhibited potent inhibition of cell proliferation in KATOIII and SNU-5 cells,with half-maximal growth inhibitory concentration(GI50)values of 250.8 and 516.3 nM,respectively.A significant elevation in the early phase apoptosis(28.53%in KATOIII cells and 26.85%in SNU-5 cells)and late phase apoptosis(17.37%in KATOIII cells and 10.05%in SNU-5 cells)were observed with SBL-JP-0004 treatment compared to 2.1%and 2.83%in their respective ***:The results highlight SBL-JP-0004 as a promising dual inhibitor targeting jak2 and PI3KCD kinases for treating GC and warrant further preclinical and clinical investigations to validate its utility in clinical settings.

关键词： Gastric cancer(GC) Dual inhibition jak2 PI3KCD SBL-JP-0004 Molecular docking Molecular dynamics simulation

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jak2、CALR、MPL共表达原发性血小板增多症1例并文献复习

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安徽医药 2025年第1期29卷 129-131页

作者：张海亚王彦丽李丽接贵涛潍坊医学院临床医学院山东潍坊261000 临沂市中心医院血液科山东临沂276400

目的探讨1例CALR、jak2及MPL 3个驱动基因突变阳性的原发性血小板增多症(ET)病人的临床及实验室特征,以提示临床医生在本病的诊断过程中对相关驱动基因突变进行更为精确的检测。方法2022年2月17日收集临沂市中心医院原发性血小板增多症... 详细信息

目的探讨1例CALR、jak2及MPL 3个驱动基因突变阳性的原发性血小板增多症(ET)病人的临床及实验室特征,以提示临床医生在本病的诊断过程中对相关驱动基因突变进行更为精确的检测。方法2022年2月17日收集临沂市中心医院原发性血小板增多症病人骨髓液送检济南金域医学检验中心,采用二代测序技术检测本例ET病人的jak2、CALR和MPL基因突变,并结合文献分析jak2、CALR、MPL 3个驱动基因突变均表达的临床及实验室特征。结果病人检测到jak2、CALR及MPL 3个驱动基因突变阳性,表现为血小板增高、红细胞计数和血红蛋白正常。结论为了进一步提高对ET乃至骨髓增殖性肿瘤的认识,需要在诊断过程中尽可能使用更为精确的二代测序对其基因突变进行检测。

关键词：血小板增多,原发性基因突变 jak2 CALR MPL 骨髓增殖性肿瘤

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Design,synthesis and SAR study of 2-aminopyridine derivatives as potent and selective jak2 inhibitors

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Chinese Chemical Letters 2022年第6期33卷 2969-2974页

作者： Dandan Liu Huan Ge Fangling Xu Yufang Xu Wenjun Liu Honglin Li Lili Zhu Yanyan Diao Zhenjiang Zhao Shanghai Key Laboratory of New Drug Design School of PharmacyEast China University of Science and TechnologyShanghai 200237China Research and Development Department Jiangzhong Pharmaceutical Co.Ltd.Nanchang 330096China

The abnormal activation of jak2 kinase is closely related to the occurrence and progression of myeloproliferative neoplasms(MPNs).At present,there is still an obvious unmet medical need for selective jak2 inhibitors in *** this paper,a class of 2-aminopyridine derivatives as potent and selective jak2 inhibitors was obtained by combining drug design,synthesis and structure-activity relationship studies based on the previously identified lead *** them,21 b exhibited high inhibitory activity against jak2 with an IC_(50)of 9 nmol/L,moreover,it showed 276-and 184-fold selectivity over jak1 and jak3,***,21 b had a significant antiproliferative activity against HEL cells,and also inhibited the phosphorylation of jak2 and its down-stream signaling *** results indicated that2-aminopyridine compound 21 b had the potential to be developed as a selective jak2 inhibitor for further study.

关键词： jak2 Selectivity Inhibitors Cancer Structure-activity relationships

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NT157 has antineoplastic effects and inhibits IRS1/2 and STAT3/5 in jak2^(V617F)-positive myeloproliferative neoplasm cells

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Signal Transduction and Targeted Therapy 2020年第1期5卷 2440-2449页

作者： Bruna Alves Fenerich Jaqueline Cristina Fernandes Ana Paula Nunes Rodrigues Alves Juan Luiz Coelho-Silva Renata Scopim-Ribeiro Priscila Santos Scheucher Christopher A.Eide Cristina E.Tognon Brian J.Druker Eduardo Magalhães Rego João Agostinho Machado-Neto Fabiola Traina Department of Medical Images Hematologyand Clinical OncologyUniversity of Sao Paulo at Ribeirao Preto Medical SchoolRibeirao PretoSao PauloBrazil Center for Cell-Based Therapy Sao Paulo Research FoundationRibeirao PretoSao PauloBrazil Knight Cancer Institute Oregon Health&Science UniversityPortlandORUSA Howard Hughes Medical Institute PortlandORUSA Department of Internal Medicine University of Sao Paulo Medical SchoolSao PauloBrazil Department of Pharmacology Institute of Biomedical Sciences of the University of Sao PauloSao PauloBrazil

Recent data indicate that IGF1R/IRS signaling is a potential therapeutic target in BCR-ABL1-negative myeloproliferative neoplasms(MPN);in this pathway,IRS2 is involved in the malignant transformation induced by jak2^(V617F),and upregulation of IGF1R signaling induces the MPN ***157,a synthetic compound designed as an IGF1R-IRS1/2 inhibitor,has been shown to induce antineoplastic effects in solid ***,we aimed to characterize the molecular and cellular effects of NT157 in jak2^(V617F)positive MPN cell lines(HEL and SET2)and primary patient hematopoietic *** jak2^(V617F)cell lines,NT157 decreased cell viability,clonogenicity,and cell proliferation,resulting in increases in apoptosis and cell cycle arrest in the G2/M phase(p2,jak2/STAT,and NFκB signaling,and it activated the AP-1 complex,downregulated four oncogenes(CCND1,MYB,WT1,and NFKB1),and upregulated three apoptotic-related genes(CDKN1A,FOS,and JUN)(pjak2/STAT-independent ***157 inhibited erythropoietin-independent colony formation in cells from polycythemia vera patients(p2 proteins may represent a promising therapeutic strategy for MPN.

关键词： jak2 IGF1R neoplasms STAT3

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Targeting polarized phenotype of microglia via IL6/jak2/ STAT3 signaling to reduce NSCLC brain metastasis

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Signal Transduction and Targeted Therapy 2022年第3期7卷 869-880页

作者： Yu Jin Yalin Kang Minghuan Wang Bili Wu Beibei Su Han Yin Yang Tang Qianxia Li Wenjie Wei Qi Mei Guangyuan Hu Veronika Lukacs-Kornek Jian Li Kongming Wu Xianglin Yuan Wei Wang Department of Oncology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030 Hubei ProvinceChina Department of Neurology Tongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan 430030 Hubei ProvinceChina Institute of Experimental Immunology University Clinic of Rheinische Friedrich-Wilhelms-UniversityBonnGermany

Tumor-associated macrophages have emerged as crucial factors for *** are indispensable components of the brain microenvironment and play vital roles in brain metastasis(BM).However,the underlying mechanism of how acti... 详细信息

关键词： metastasis jak2 NSCLC STAT3

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Pyrrolidine dithiocarbamate alleviates the anti-tuberculosis drug-induced liver injury through jak2/STAT3 signaling pathway:An experimental study

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Asian Pacific Journal of Tropical Medicine 2017年第5期10卷 493-496页

作者： Hong Zhang Yang Liu Li-Kun Wang Na Wei Internal Medicine Department No.2 Linyi Chest Hospital in Shandong ProvinceLinyi CityShandong Province 276034China Child Healthcare Department Linyi Chest Hospital in Shandong ProvinceLinyi CityShandong Province 276034China Infectious Disease Department No.6 Ward Linyi People's Hospital in Shandong ProvinceLinyi CityShandong Province 276034China Laboratory Department Linyi Chest Hospital in Shandong ProvinceLinyi CityShandong Province 276034China

Objective:To study the effect of pyrrolidine dithiocarbamate(PDTC) on the anti-tuberculosis drug-induced liver injury and the molecular mechanism. Methods:Clean male SD rats were selected as experimental animals and randomly divided into normal group,model group,PDTC group and AG490 group. Animal model of anti-tuberculosis drug-induced liver injury was established by intragastric administration isoniazid + rifampicin. PDTC group received intraperitoneal injection of PDTC,and AG490 group received intraperitoneal injection of AG490. Twenty-eight days after intervention,the rats were executed,and the liver injury indexes,inflammation indexes and oxidative stress indexes in serum as well as jak2/STAT3 expression,liver injury indexes,inflammation indexes and oxidative stress indexes in liver tissue were determined. Results:p-jak2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissue as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of model group were significantly higher than those of normal group while p-jak2,p-STAT3,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA expression in liver tissu as well as TBIL,ALT,AST,γ-GT,TNF-α,IL-1β,IL-6,ROS,8-OHdG and MDA levels in serum of PDTC group and AG490 group were significantly lower than those of model group. Conclusions:PDTC can inhibit the inflammation and oxidative stress mediated by jak2/STAT3 signaling pathway to alleviate the anti-tuberculosis drug-induced liver injury.

关键词： Drug-induced liver injury Anti-tuberculosis drug Pyrrolidine dithiocarbamate jak2 STAT3

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Long term follow-up after liver transplantation from a jak2 mutation positive donor

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Hepatobiliary Surgery and Nutrition 2019年第2期8卷 189-191页

作者： Alejandro Lazo-Langner Peter Ainsworth Vivian McAlister Department of Medicine Division of HematologyWestern UniversityLondonONCanada Department of Epidemiology and Biostatistics Western UniversityLondonONCanada Department of Oncology Western UniversityLondonONCanada Department of Pathology and Laboratory Medicine Western UniversityLondonONCanada Department of Surgery Western UniversityLondonONCanada

Introduction Philadelphia-negative myeloproliferative neoplasms(MPN),including polycythemia vera(PV),essential thrombocythemia(ET),and primary myelofibrosis(PMF),are characterized by the presence of mutations involving the Janus Kinase 2(jak2),calreticulin(CALR)or myeloproliferative leukemia virus oncogene(MPL)genes(1).Of these,the jak2 V617F gain-of-function mutation is the most frequently found and is present in>95%of patients with PV and in about 60%of those with ET or PMF whereas jak2 exon 12 mutations are found in the remaining PV patients(2).jak2 V617F somatic mutations have been detected in granulocytes and platelets and therefore they could potentially be transmitted to recipients of solid organ transplants(3)and in fact the presence of the jak2 V617F mutation has been detected in otherwise healthy blood donors(4,5).

关键词： jak2 neoplasms patients

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Virtual screening and optimization of typeⅡ inhibitors of jak2 from a natural product library

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中国药理学与毒理学杂志 2015年第S1期29卷 98-99页

作者： Dik-LungMA DanielShiu-HinCHAN GuoWEI Hai-jingZHONG HuiYANG LaiToLEUNG ElizabethA.GULLEN PaulineChIU Yung-ChiCHENG Chung-hangLEUNG Department of Chemistry Hong Kong Baptist University Hong Kong China Department of Chemistry and the State Key Laboratory of Synthetic Chemistry University of Hong Kong Hong Kong China State Key Laboratory of Quality Research in Chinese Medicine Institute of Chinese Medical Sciences University of Macao Macao China Department of Pharmacology Yale University School of Medicine New Haven CT 06520 USA

OBJECTIVE To utilize a structure-based lead optimization approach to generate novel natural product-like typeⅡ inhibitors of jak2 using the DOLPHIN *** Initially,the DOLHPIN computational protocol was employed to convert an active(DFG-in)conformation of jak2 into a typeⅡ-compatible conformation,which was used as a model for the structure-based virtual screening of 150 000 natural product-like compounds in *** novel biflavonoid analogues were designed and synthesized based on the structure of lead compound and then tested for jak2 and STAT3 inhibitory activity,cytotoxicity and HCV antiviral *** The top eleven highest-scoring compounds were generated from the initial high-throughput virtual *** 1a,a biflavonoid from the Chinese plant Gingko biloba,emerged as a promising candidate for further biological *** dose-response experiments,amentoflavone 1ainhibited jak2 activity in a concentration dependent fashion with an IC50 value of 5μmol·*** a proof-of-concept,we designed nine analogues 1b-1j with the addition of one or more aliphatic side chains to the biflavonoid scaffold of *** octyl(C8)analogue 1bdisplayed superior potency against jak2 activity and HCV activity compared to the parent compound 1a,validating the structure-based lead optimization approach used in this ***,kinetic analysis indicated that analogue 1bexhibited a non-competitive mode of inhibition,suggesting that this compound may be a putative typeⅡ inhibitor of *** Amentoflavone 1ahas been identified as a jak2 inhibitor by structure-based virtual screening of a natural product *** silico optimization using the DOLPHIN model yielded analogues with enhanced potency against jak2 activity and HCV activity in *** modeling and kinetic experiments suggested that the analogues may function as typeⅡ inhibitors of jak2.

关键词： jak2 natural products virtual screening structure-

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Zeylenone promotes apoptosis of chronic myelogenous leukemia-derived K562 cells by a mechanism involving jak2 and src kinase

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中国药理学与毒理学杂志 2016年第10期30卷 1069-1070页

作者： HUO Xiao-wei LIAO Yong-hong TIAN Yu GAO Li LIU Dong-yu LI Li-yong CAO Li Institute of Medicinal Plant Development Chinese Academy of Medical Sciences and Peking Union Medical College

OBJECTIVE The present study was designed to investigate anticancer effect of zeylenone(Zey)on K562 cells derived from chronic myelogenous leukemia(CML)both in vitro and in vivo,followed by exploring the underlying *** Initially,the effects of Zey on cel viability,proliferation,and apoptosis were measured in K562 cells by MTT,soft agar assay,AO/EB staining,hoechst 33258 staining and flow cytometric analysis after they were treated with Zey for indicated time,the involving signaling pathways were then investigated by JC-1,real-time quantitative polymerase chain reaction(RT-q PCR),Western blotting and immunofluorescence ***,the in vivo anti-tumoractivity of Zey was assessed with nude xenografts and the involving mechanism was confirmed by immunohistochemical(IHC)and histopathological *** We identified that Zey dose-dependently decreased cell viability,colony formation and expression of Proliferating Cell Nuclear Antigen(PCNA),and significantly induced K562 cell apoptosis via regulating Bcl-2 family members,decreasing mitochondrial transmembrane potential,and activating caspase-3,caspase-9,and caspase-8(Pjak2 and Src and downregulated their downstream proteins,including stat3,PI3K/AKT/m TOR,and ERK1/2 signaling pathways(P2cells through decreasing expression of jak2 and *** Our data demonstrated that Zey substantially suppressed K562 cells both in vitro and in vivo through jak2 and Src *** findings suggest the potential of Zey as an effective anticancer agent in CML treatment.

关键词： zeylenone apoptosis K562 cells jak2 Src

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NOK通过jak2依赖性方式激活STAT3信号通路(英文)

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生物化学与生物物理进展 2008年第2期35卷 143-150页

作者：李颖华戎煜常智杰刘力清华大学医学院清华大学生物科学与技术系生物膜与膜生物技术国家重点实验室北京100084 中国医学科学院基础医学研究所北京协和医学院基础学院北京100005

NOK能激活包含jak-STAT信号通路在内的多种促细胞有丝分裂信号通路.研究发现,在人胚肾细胞(HEK293T)中,NOK与STAT3具有直接的相互作用.进一步的实验表明,NOK能同STAT3蛋白除螺旋结构域及C端结构域外的其他4个结构域发生相互作用,而NOK... 详细信息

NOK能激活包含jak-STAT信号通路在内的多种促细胞有丝分裂信号通路.研究发现,在人胚肾细胞(HEK293T)中,NOK与STAT3具有直接的相互作用.进一步的实验表明,NOK能同STAT3蛋白除螺旋结构域及C端结构域外的其他4个结构域发生相互作用,而NOK的胞内区则介导了NOK同STAT3的相互作用.同时,免疫共沉淀实验显示,NOK能与jak2发生相互作用.重要的是,共同表达NOK与jak2蛋白对STAT3信号通路能产生一种非常显著的协同激活作用,但当共同表达NOK和jak2的激酶活性缺失突变体时,并不产生这种协同激活效应.综上,实验结果显示,NOK可能同STAT3和jak2形成一个复合物,通过jak2依赖性方式激活STAT3信号通路.

关键词： NOK jak2 STAT3 协同效应免疫共沉淀信号激活

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