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Discovery of SIAIS178 as an Effective BCR-ABL Degrader by Recruiting Von Hippel-Lindau (VHL) E3 Ubiquitin Ligase | |
2019-10-24 | |
发表期刊 | JOURNAL OF MEDICINAL CHEMISTRY |
ISSN | 0022-2623 |
EISSN | 1520-4804 |
卷号 | 62期号:20页码:9281-9298 |
发表状态 | 已发表 |
DOI | 10.1021/acs.jmedchem.9b01264 |
摘要 | The 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. |
URL | 查看原文 |
收录类别 | SCI ; SCIE ; IC |
资助项目 | China Postdoctoral Science Foundation[2018M642112] ; China Postdoctoral Science Foundation[2018M642110] ; China Postdoctoral Science Foundation[2018M632181] ; China Postdoctoral Science Foundation[2019M651609] |
WOS研究方向 | Pharmacology & Pharmacy |
WOS类目 | Chemistry, Medicinal |
WOS记录号 | WOS:000492801800025 |
出版者 | AMER CHEMICAL SOC |
WOS关键词 | INDUCED PROTEIN-DEGRADATION ; CHRONIC MYELOID-LEUKEMIA ; KINASE INHIBITORS ; CHIMERIC MOLECULES ; PROTAC DESIGN ; STEM-CELLS ; RESISTANCE ; MUTATIONS ; CONJUGATION ; BROMODOMAIN |
原始文献类型 | Article |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/80502 |
专题 | 生命科学与技术学院_硕士生 免疫化学研究所_特聘教授组_抗体结构学实验室 免疫化学研究所_特聘教授组_抗体化学实验室 科技发展处 生命科学与技术学院_博士生 免疫化学研究所_PI研究组_杨贝组 |
共同第一作者 | Ren, Chaowei; Liu, Linyi |
通讯作者 | Yin, Qianqian; Yang, Xiaobao; Jiang, Biao |
作者单位 | 1.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 |
第一作者单位 | 免疫化学研究所 |
通讯作者单位 | 免疫化学研究所 |
第一作者的第一单位 | 免疫化学研究所 |
推荐引用方式 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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