Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

  • J Med Chem. 2018 May 10;61(9):4249-4255. doi: 10.1021/acs.jmedchem.7b01655.
Chelsea E Powell  1 ,  Yang Gao  2 ,  Li Tan  1 ,  Katherine A Donovan  1 ,  Radosław P Nowak  1 ,  Amanda Loehr  2 ,  Magda Bahcall ,  Eric S Fischer  1 ,  Pasi A Jänne ,  Rani E George  2 ,  Nathanael S Gray  1
Affiliations
  • 1. Department of Biological Chemistry & Molecular Pharmacology , Harvard Medical School , Boston , Massachusetts 02115 , United States.
  • 2. Department of Pediatric Hematology and Oncology , Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School , Boston , Massachusetts 02215 , United States.
PMID: 29660984 DOI: 10.1021/acs.jmedchem.7b01655
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).

Products