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

Autor: Li Yan, Xiaobao Yang, Jianshui Zhang, Haifan Lin, Ren Chaowei, Kong Ying, Yuedong Zhou, Xing Qiu, Chen Jinju, Biao Jiang, Xiaoling Song, Sun Ning, Hui Zhong
Rok vydání: 2020
Předmět:
Lung Neoplasms
Brigatinib
medicine.drug_class
medicine.medical_treatment
Antineoplastic Agents
01 natural sciences
Targeted therapy
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Drug Development
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
hemic and lymphatic diseases
Drug Discovery
medicine
Humans
Anaplastic lymphoma kinase
Anaplastic Lymphoma Kinase
Protein Kinase Inhibitors
Cell Proliferation
030304 developmental biology
Pharmacology
0303 health sciences
Dose-Response Relationship
Drug
Molecular Structure
010405 organic chemistry
Organic Chemistry
Proteolysis targeting chimera
Cancer
General Medicine
medicine.disease
Fusion protein
0104 chemical sciences
Molecular Docking Simulation
ALK inhibitor
HEK293 Cells
chemistry
Drug Resistance
Neoplasm
Cancer research
Drug Screening Assays
Antitumor
Growth inhibition
Zdroj: European Journal of Medicinal Chemistry. 193:112190
ISSN: 0223-5234
DOI: 10.1016/j.ejmech.2020.112190
Popis: 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.
Databáze: OpenAIRE
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