2. Academic Validation
  3. Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile

Discovery of a Brigatinib Degrader SIAIS164018 with Destroying Metastasis-Related Oncoproteins and a Reshuffling Kinome Profile

  • J Med Chem. 2021 Jul 8;64(13):9152-9165. doi: 10.1021/acs.jmedchem.1c00373.
Chaowei Ren 1 2 3,  Ning Sun 1 4,  Haixia Liu 1 5 3,  Ying Kong 6,  Renhong Sun 1 4,  Xing Qiu 7,  Jinju Chen 6,  Yan Li 6,  Jianshui Zhang 6,  Yuedong Zhou 6,  Hui Zhong 1 8,  Qianqian Yin 1,  Xiaoling Song 1,  Xiaobao Yang 1,  Biao Jiang 1 5 7
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai 201210, China.
  • 2 School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
  • 5 School of Physical Science and Technology, ShanghaiTech University, Shanghai 201210, China.
  • 6 Jing Medicine Technology (Shanghai), Ltd., Y Building, Shanghai 201210, China.
  • 7 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China.
  • 8 School of Pharmaceutical Engineering and Life Science, Changzhou University, Changzhou, Jiangsu 213164, China.
PMID: 34138566 DOI: 10.1021/acs.jmedchem.1c00373
Abstract

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.

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