su-11248 and Leukemia--Myelogenous--Chronic--BCR-ABL-Positive

In modern cancer therapy, the use of small organic molecules against receptor tyrosine kinases (RTKs) has been shown to be a valuable strategy. The association of cancer cells with dysregulated signaling pathways linked to RTKs represents a key element in targeted cancer therapies. The tyrosine kinase mast/stem cell growth factor receptor KIT is an example of a clinically relevant RTK. KIT is targeted for cancer therapy in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). However, acquired resistance mutations within the catalytic domain decrease the efficacy of this strategy and are the most common cause of failed therapy. Here, we present the structure-based design and synthesis of novel type II kinase inhibitors to overcome these mutations in KIT. Biochemical and cellular studies revealed promising molecules for the inhibition of mutated KIT.

Topics: Drug Resistance, Neoplasm; Gastrointestinal Neoplasms; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-kit; Receptor Protein-Tyrosine Kinases; Structure-Activity Relationship

Mutations in the catalytic domain at the gatekeeper position represent the most prominent drug-resistant variants of kinases and significantly impair the efficacy of targeted cancer therapies. Understanding the mechanisms of drug resistance at the molecular and atomic levels will aid in the design and development of inhibitors that have the potential to overcome these resistance mutations. Herein, by introducing adaptive elements into the inhibitor core structure, we undertake the structure-based development of type II hybrid inhibitors to overcome gatekeeper drug-resistant mutations in cSrc-T338M, as well as clinically relevant tyrosine kinase KIT-T670I and Abl-T315I variants, as essential targets in gastrointestinal stromal tumors (GISTs) and chronic myelogenous leukemia (CML). Using protein X-ray crystallography, we confirm the anticipated binding mode in cSrc, which proved to be essential for overcoming the respective resistances. More importantly, the novel compounds effectively inhibit clinically relevant gatekeeper mutants of KIT and Abl in biochemical and cellular studies.

Topics: Cell Line, Tumor; Crystallography, X-Ray; Drug Design; Drug Resistance, Neoplasm; Humans; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Mutation; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-abl; Proto-Oncogene Proteins c-kit; Structure-Activity Relationship