Chemically Induced Degradation of Anaplastic Lymphoma Kinase (ALK)

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).