Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile
2021-07-08
发表期刊JOURNAL OF MEDICINAL CHEMISTRY (IF:6.8[JCR-2023],7.1[5-Year])
ISSN0022-2623
EISSN1520-4804
卷号64期号:13页码:9152-9165
发表状态已发表
DOI10.1021/acs.jmedchem.1c00373
摘要

Proteolysis-targeting chimera (PROTAC) is an attractive technology in drug discovery. Canonically, targets act as a basic starting point in the most previous PROTAC design. Here, we designed degraders considering from the view of clinical benefits. With this novel design, Brigatinib was turned into a degrader SIAIS164018 and endowed with unique features. First, SIAIS164018 could degrade not only ALK fusion proteins in activating or G1202R-mutated form but also mutant EGFR with L858R + T790M, which are two most important targets in non-small-cell lung cancer. Second, SIAIS164018 strongly inhibited cell migration and invasion of Calu-1 and MDA-MB-231. Third and surprisingly, SIAIS164018 degrades several important oncoproteins involved in metastasis such as FAK, PYK2, and PTK6. Interestingly, SIAIS164018 reshuffled the kinome ranking profile when compared to Brigatinib. Finally, SIAIS164018 is orally bioavailable and well tolerated in vivo. SIAIS164018 is an enlightening degrader for us to excavate the charm of protein degradation.

收录类别SCIE ; IC
WOS研究方向Pharmacology & Pharmacy
WOS类目Chemistry, Medicinal
WOS记录号WOS:000672729800017
出版者AMER CHEMICAL SOC
原始文献类型Article
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/127780
专题生命科学与技术学院_博士生
免疫化学研究所_特聘教授组_抗体化学实验室
科技发展处
物质科学与技术学院_博士生
共同第一作者Sun, Ning
通讯作者Song, Xiaoling; 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.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
4.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China;
5.Icahn Sch Med Mt Sinai, New York, NY 10029 USA;
6.ShanghaiTech Univ, Sch Phys Sci & Technol, Shanghai 201210, Peoples R China;
7.Jing Med Technol Shanghai Ltd, Shanghai 201210, Peoples R China;
8.Chinese Acad Sci, Shanghai Inst Organ Chem, CAS Key Lab Synthet Chem Nat Subst, Shanghai 200032, Peoples R China;
9.Changzhou Univ, Sch Pharmaceut Engn & Life Sci, Changzhou 213164, Jiangsu, Peoples R China
第一作者单位免疫化学研究所;  生命科学与技术学院
通讯作者单位免疫化学研究所;  物质科学与技术学院
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
Ren, Chaowei,Sun, Ning,Liu, Haixia,et al. Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile[J]. JOURNAL OF MEDICINAL CHEMISTRY,2021,64(13):9152-9165.
APA Ren, Chaowei.,Sun, Ning.,Liu, Haixia.,Kong, Ying.,Sun, Renhong.,...&Jiang, Biao.(2021).Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile.JOURNAL OF MEDICINAL CHEMISTRY,64(13),9152-9165.
MLA Ren, Chaowei,et al."Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile".JOURNAL OF MEDICINAL CHEMISTRY 64.13(2021):9152-9165.
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