Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK).
Chelsea E PowellYang GaoLi TanKatherine A DonovanRadosław P NowakAmanda LoehrMagda BahcallEric S FischerPasi A JänneRani E GeorgeNathanael S GrayPublished in: Journal of medicinal chemistry (2018)
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).
Keyphrases
- advanced non small cell lung cancer
- small molecule
- single cell
- diffuse large b cell lymphoma
- cell therapy
- small cell lung cancer
- poor prognosis
- tyrosine kinase
- high glucose
- protein kinase
- emergency department
- drug induced
- diabetic rats
- oxidative stress
- multiple myeloma
- bone marrow
- epidermal growth factor receptor
- endothelial cells
- long non coding rna
- protein protein