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Cancer Cell. 2019 May 13;35(5):738-751.e9. doi: 10.1016/j.ccell.2019.04.006.

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

Author information

1
Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA.
2
Emerald Biostructures, Bainbridge Island, WA 98110, USA.
3
Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA.
4
The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX 77030, USA.
5
Princess Margaret Cancer Centre, Cancer Clinical Research Unit, Toronto, ON, Canada.
6
Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA. Electronic address: dflynn@deciphera.com.

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.

KEYWORDS:

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

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