2. Academic Validation
  3. Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance

Development of a Brigatinib degrader (SIAIS117) as a potential treatment for ALK positive cancer resistance

  • Eur J Med Chem. 2020 May 1;193:112190. doi: 10.1016/j.ejmech.2020.112190.
Ning Sun 1,  Chaowei Ren 1,  Ying Kong 2,  Hui Zhong 3,  Jinju Chen 2,  Yan Li 2,  Jianshui Zhang 2,  Yuedong Zhou 2,  Xing Qiu 4,  Haifan Lin 5,  Xiaoling Song 6,  Xiaobao Yang 7,  Biao Jiang 8
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China.
  • 2 Jing Medicine Technology (Shanghai), Ltd., Y building, 230 Haike Road, Shanghai, 201210, China.
  • 3 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; Changzhou University, Changzhou, Jiangsu, 213164, China.
  • 4 CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China.
  • 5 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; Yale Stem Cell Center, Yale University, New Haven, CT, 06511, USA. Electronic address: Linhf@shanghaitech.edu.cn.
  • 6 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. Electronic address: songxl@shanghaitech.edu.cn.
  • 7 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China. Electronic address: yangxb@shanghaitech.edu.cn.
  • 8 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai, 201210, China; CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China. Electronic address: jiangbiao@shanghaitech.edu.cn.
PMID: 32179332 DOI: 10.1016/j.ejmech.2020.112190
Abstract

EML4-ALK and NPM-ALK fusion proteins possess constitutively activated ALK (anaplastic lymphoma kinase) activity, which in turn leads to the development of non-small cell lung Cancer and anaplastic large-cell lymphomas (ALCLs). FDA-approved ALK inhibitor drugs cause significant Cancer regression. However, drug resistance eventually occurs and it becomes a big obstacle in clinic. Novel proteolysis targeting chimera (PROTAC) technology platform provides a potential therapeutic strategy for drug resistance. Herein, we designed and synthesized a series of ALK PROTACs based on Brigatinib and VHL-1 conjunction, and screened SIAIS117 as the best degrader which not only blocked the growth of SR and H2228 Cancer cell lines, but also degraded ALK protein. In addition, SIAIS117 also showed much better growth inhibition effect than Brigatinib on 293T cell line that exogenously expressed G1202R-resistant ALK proteins. Furthermore, it also degraded G1202R mutant ALK protein in vitro. At last, it has the potentially anti-proliferation ability of small cell lung Cancer. Thus, we have successfully generated the degrader SIAIS117 that can potentially overcome resistance in Cancer Targeted Therapy.

Keywords

ALCL; ALK; Brigatinib; Degrader; NSCLC; PROTAC; Resistance; VHL.

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