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

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

GIST KIT PDGFRA conformational switch control imatinib mastocytosis regorafenib resistance ripretinib sunitinib

Journal

Cancer cell

ISSN: 1878-3686

Titre abrégé: Cancer Cell

Pays: United States

ID NLM: 101130617

Informations de publication

Date de publication:
13 05 2019

Historique:

received: 09 11 2018

revised: 18 02 2019

accepted: 15 04 2019

entrez: 16 5 2019

pubmed: 16 5 2019

medline: 15 2 2020

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ccell.2019.04.006 PMID: 31085175

pubmed: 31085175

pii: S1535-6108(19)30201-6

doi: 10.1016/j.ccell.2019.04.006

pii:

doi:

Substances chimiques

Antineoplastic Agents 0

Protein Kinase Inhibitors 0

KIT protein, human EC 2.7.10.1

Proto-Oncogene Proteins c-kit EC 2.7.10.1

Receptor, Platelet-Derived Growth Factor alpha EC 2.7.10.1

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

738-751.e9

Subventions

Organisme : BLRD VA

ID : I01 BX000338

Pays : United States

Commentaires et corrections

Type : CommentIn