Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

J Med Chem. 2018 May 10;61(9):4249-4255. doi: 10.1021/acs.jmedchem.7b01655. Epub 2018 Apr 24.

Abstract

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).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase / antagonists & inhibitors
  • Anaplastic Lymphoma Kinase / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Humans
  • Lung Neoplasms / pathology
  • Protein Kinase Inhibitors / pharmacology*
  • Proteolysis / drug effects*
  • Pyrimidines / pharmacology
  • Sulfones / pharmacology

Substances

  • NVP-TAE684
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Sulfones
  • Anaplastic Lymphoma Kinase
  • ceritinib