Department of Biological Chemistry & Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
Department of Pediatric Hematology and Oncology , Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School , Boston , Massachusetts 02215 , United States.
J Med Chem. 2018 May 10;61(9):4249-4255. doi: 10.1021/acs.jmedchem.7b01655. Epub 2018 Apr 24.
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).
我们介绍了第一种能够诱导间变性淋巴瘤激酶 (ALK) 降解的小分子降解剂的开发，包括在非小细胞肺癌 (NSCLC)、间变大细胞淋巴瘤 (ALCL) 和神经母细胞瘤 (NB) 细胞系中。这些降解剂是通过将已知的嘧啶基 ALK 抑制剂 TAE684 或 LDK378 与 cereblon 配体来那度胺偶联而成。我们证明，在某些细胞类型中，药物转运蛋白 ABCB1 的表达会降低降解剂的效力。此外，蛋白质组学分析表明，这些化合物还促进了其他激酶的降解，包括 PTK2（FAK）、Aurora A、FER 和 RPS6KA1（RSK1）。
