Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants.

Abstract

Ripretinib (DCC-2618) was designed to inhibit the full spectrum of mutant KIT and PDGFRA kinases found in cancers and myeloproliferative neoplasms, particularly in gastrointestinal stromal tumors (GISTs), in which the heterogeneity of drug-resistant KIT mutations is a major challenge. Ripretinib is a "switch-control" kinase inhibitor that forces the activation loop (or activation "switch") into an inactive conformation. Ripretinib inhibits all tested KIT and PDGFRA mutants, and notably is a type II kinase inhibitor demonstrated to broadly inhibit activation loop mutations in KIT and PDGFRA, previously thought only achievable with type I inhibitors. Ripretinib shows efficacy in preclinical cancer models, and preliminary clinical data provide proof-of-concept that ripretinib inhibits a wide range of KIT mutants in patients with drug-resistant GISTs.

• Authors: Bryan D Smith, Michael D Kaufman, Wei-Ping Lu, Anu Gupta, Cynthia B Leary, Scott C Wise, Thomas J Rutkoski, Yu Mi Ahn, Gada Al-Ani, Stacie L Bulfer, Timothy M Caldwell, Lawrence Chun, Carol L Ensinger, Molly M Hood, Arin McKinley, William C Patt, Rodrigo Ruiz-Soto, Ying Su, Hanumaiah Telikepalli, Ajia Town, Benjamin A Turner, Lakshminarayana Vogeti, Subha Vogeti, Karen Yates, Filip Janku, Albiruni Ryan Abdul Razak, Oliver Rosen, Michael C Heinrich, Daniel L Flynn
• Journal: Cancer cell (Cancer Cell) Vol. 35 Issue 5 Pg. 738-751.e9 (05 13 2019) ISSN: 1878-3686 [Electronic] United States
• PMID: 31085175 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Protein Kinase Inhibitors
• KIT protein, human
• Proto-Oncogene Proteins c-kit
• Receptor, Platelet-Derived Growth Factor alpha

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• CHO Cells
• Cell Line
• Cell Line, Tumor
• Cricetulus
• Drug Resistance, Neoplasm (drug effects, genetics)
• Gastrointestinal Neoplasms (drug therapy, genetics)
• HCT116 Cells
• Human Umbilical Vein Endothelial Cells
• Humans
• Mice
• Mice, Inbred BALB C
• Mice, Inbred NOD
• Mice, Nude
• Mice, SCID
• Mutation (drug effects, genetics)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-kit (genetics)
• Receptor, Platelet-Derived Growth Factor alpha (genetics)