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

Autor:	Smith BD; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Kaufman MD; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Lu WP; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Gupta A; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Leary CB; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Wise SC; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Rutkoski TJ; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Ahn YM; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Al-Ani G; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Bulfer SL; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Caldwell TM; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Chun L; Emerald Biostructures, Bainbridge Island, WA 98110, USA., Ensinger CL; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Hood MM; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., McKinley A; Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA., Patt WC; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Ruiz-Soto R; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Su Y; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Telikepalli H; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Town A; Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA., Turner BA; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Vogeti L; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Vogeti S; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Yates K; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Janku F; The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX 77030, USA., Abdul Razak AR; Princess Margaret Cancer Centre, Cancer Clinical Research Unit, Toronto, ON, Canada., Rosen O; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA., Heinrich MC; Portland VA Medical Center and Oregon Health & Science University Knight Cancer Institute, Portland, OR 97239, USA., Flynn DL; Deciphera Pharmaceuticals, Inc., Waltham, MA 02451, USA. Electronic address: dflynn@deciphera.com.
Jazyk:	angličtina
Zdroj:	Cancer cell [Cancer Cell] 2019 May 13; Vol. 35 (5), pp. 738-751.e9.
DOI:	10.1016/j.ccell.2019.04.006
Abstrakt:	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. (Copyright © 2019 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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