期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 61, 期 9, 页码 4249-4255出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.7b01655
关键词
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资金
- National Institutes of Health (NIH) [R01 CA136851-08, R01 CA148688, R01 CA214608-01]
- NIH [5 T32 GM095450-04, 2 T32 GM007306-40]
- Friends for Life Neuroblastoma Fellowship
We present the development of the first small molecule degraders that can induce anaplastic lymphoma kinase (ALK) degradation, including in non-small-cell lung cancer (NSCLC), anaplastic large-cell lymphoma (ALCL), and neuroblastoma (NB) cell lines. These degraders were developed through conjugation of known pyrimidine-based ALK inhibitors, TAE684 or LDK378, and the cereblon ligand pomalidomide. We demonstrate that in some cell types degrader potency is compromised by expression of drug transporter ABCB1. In addition, proteomic profiling demonstrated that these compounds also promote the degradation of additional kinases including PTK2 (FAK), Aurora A, FER, and RPS6KA1 (RSK1).
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