Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase
Zhao, Quanju1,3; Ren, Chaowei1,2; Liu, Linyi1,3; Chen, Jinju1; Shao, Yubao4; Sun, Ning1,3; Sun, Renhong1,3; Kong, Ying1; Ding, Xinyu1; Zhang, Xianfang1; Xu, Youwei1; Yang, Bei1; Yin, Qianqian1; Yang, Xiaobao1; Jiang, Biao1,5
2019-10-24
Source PublicationJOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
Volume62Issue:20Pages:9281-9298
Status已发表
DOI10.1021/acs.jmedchem.9b01264
AbstractThe oncogenic fusion protein BCR-ABL is the driving force of leukemogenesis in chronic myeloid leukemia (CML). Despite great progress for CML treatment through application of tyrosine kinase inhibitors (TKIs) against BCR-ABL, long-term drug administration and clinical resistance continue to be an issue. Herein, we described the design, synthesis, and evaluation of novel proteolysis-targeting chimeric (PROTAC) small molecules targeting BCR-ABL which connect dasatinib and VHL E3 ubiquitin ligase ligand by extensive optimization of linkers. Our efforts have yielded SIA15178 (19), which induces proper interaction between BCR-ABL and VHL ligase leading to effective degradation of BCR-ABL protein, achieves significant growth inhibition of BCR-ABL(+) leukemic cells in vitro, and induces substantial tumor regression against K562 xenograft tumors in vivo. In addition, SIAIS178 also degrades several clinically relevant resistance-conferring mutations. Our data indicate that SIAI5178 as efficacious BCR-ABL degrader warrants extensive further investigation for the treatment of BCR-ABL(+) leukemia.
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Indexed BySCI ; IC
Language英语
Funding ProjectChina Postdoctoral Science Foundation[2018M642112] ; China Postdoctoral Science Foundation[2018M642110] ; China Postdoctoral Science Foundation[2018M632181] ; China Postdoctoral Science Foundation[2019M651609]
WOS Research AreaPharmacology & Pharmacy
WOS SubjectChemistry, Medicinal
WOS IDWOS:000492801800025
PublisherAMER CHEMICAL SOC
EISSN1520-4804
WOS KeywordINDUCED PROTEIN-DEGRADATION ; CHRONIC MYELOID-LEUKEMIA ; KINASE INHIBITORS ; CHIMERIC MOLECULES ; PROTAC DESIGN ; STEM-CELLS ; RESISTANCE ; MUTATIONS ; CONJUGATION ; BROMODOMAIN
Original Document TypeArticle
Citation statistics
Cited Times:5[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://kms.shanghaitech.edu.cn/handle/2MSLDSTB/80502
Collection免疫化学研究所_特聘教授组_抗体化学实验室
免疫化学研究所_特聘教授组_抗体结构学实验室
科技发展处
生命科学与技术学院_硕士生
Corresponding AuthorYin, Qianqian; Yang, Xiaobao; Jiang, Biao
Affiliation1.ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai 201210, Peoples R China
2.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China
4.Anhui Med Univ, Dept Histol & Embryol, Hefei 230032, Anhui, Peoples R China
5.Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, 345 Lingling Rd, Shanghai 200032, Peoples R China
First Author AffilicationShanghai Institute for Advanced Immunochemical Studies
Corresponding Author AffilicationShanghai Institute for Advanced Immunochemical Studies
First Signature AffilicationShanghai Institute for Advanced Immunochemical Studies
Recommended Citation
GB/T 7714
Zhao, Quanju,Ren, Chaowei,Liu, Linyi,et al. Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase[J]. JOURNAL OF MEDICINAL CHEMISTRY,2019,62(20):9281-9298.
APA Zhao, Quanju.,Ren, Chaowei.,Liu, Linyi.,Chen, Jinju.,Shao, Yubao.,...&Jiang, Biao.(2019).Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase.JOURNAL OF MEDICINAL CHEMISTRY,62(20),9281-9298.
MLA Zhao, Quanju,et al."Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase".JOURNAL OF MEDICINAL CHEMISTRY 62.20(2019):9281-9298.
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