nvp-tae684 and ceritinib

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).

Topics: Anaplastic Lymphoma Kinase; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Humans; Lung Neoplasms; Protein Kinase Inhibitors; Proteolysis; Pyrimidines; Sulfones

The synthesis, preclinical profile, and in vivo efficacy in rat xenograft models of the novel and selective anaplastic lymphoma kinase inhibitor 15b (LDK378) are described. In this initial report, preliminary structure-activity relationships (SARs) are described as well as the rational design strategy employed to overcome the development deficiencies of the first generation ALK inhibitor 4 (TAE684). Compound 15b is currently in phase 1 and phase 2 clinical trials with substantial antitumor activity being observed in ALK-positive cancer patients.

Topics: Anaplastic Lymphoma Kinase; Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dogs; Humans; Macaca fascicularis; Male; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Rats; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship; Sulfones; Xenograft Model Antitumor Assays

Topics: Anaplastic Lymphoma Kinase; Animals; Humans; Male; Neoplasms; Protein Kinase Inhibitors; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sulfones