@article{68af850a3c9c4f039fe7cdd2374c784f,
title = "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.",
keywords = "GIST, KIT, PDGFRA, conformational switch control, imatinib, mastocytosis, regorafenib, resistance, ripretinib, sunitinib",
author = "Smith, {Bryan D.} and Kaufman, {Michael D.} and Lu, {Wei Ping} and Anu Gupta and Leary, {Cynthia B.} and Wise, {Scott C.} and Rutkoski, {Thomas J.} and Ahn, {Yu Mi} and Gada Al-Ani and Bulfer, {Stacie L.} and Caldwell, {Timothy M.} and Lawrence Chun and Ensinger, {Carol L.} and Hood, {Molly M.} and Arin McKinley and Patt, {William C.} and Rodrigo Ruiz-Soto and Ying Su and Hanumaiah Telikepalli and Ajia Town and Turner, {Benjamin A.} and Lakshminarayana Vogeti and Subha Vogeti and Karen Yates and Filip Janku and {Abdul Razak}, {Albiruni Ryan} and Oliver Rosen and Heinrich, {Michael C.} and Flynn, {Daniel L.}",
note = "Funding Information: The authors thank J. Fletcher for GIST 48, GIST 430, and GIST 882 cell lines, B. Rubin for GIST T1 5R (T670I)and GIST T1 Juke (D816E), and T. Taguchi for GIST T1 KIT mutant cells. B.D.S. would like to dedicate this paper to Prof. Ronald T. Raines on the occasion of his 60th birthday. Conceptualization, D.L.F. B.D.S. M.D.K. and S.C.W.; Experimental Design, B.D.S. S.C.W. A.G. W.-P.L. S.L.B. T.J.R. M.C.H. and D.L.F.; Experimental Work and Data Interpretation, B.D.S. A.G. W.-P.L. T.J.R. G.A.-A. S.L.B. L.C. M.M.H. C.B.L. D.F.M. B.A.T. and S.V.; Chemistry, M.D.K. Y.M.A. T.M.C. C.L.E. W.C.P. H.T. L.V. T.Y. and K.Y.; Clinical Study Design and Analysis, F.J. Y.S. R.R.-S. and O.R.; Patient Treatment, F.J. and A.R.A.R.; Writing, B.D.S. O.R. M.C.H. and D.L.F. B.D.S. M.D.K. W.P.L. A.G. C.B.L. Y.M.A. G.A.A. S.L.B. T.M.C. R.R.S. Y.S. H.T. L.V. S.V. K.Y. and D.L.F. are employees and shareholders of Deciphera Pharmaceuticals. O.R. is an employee of Deciphera Pharmaceuticals. D.L.F. is founder of Deciphera Pharmaceuticals and a member of its scientific advisory board. S.C.W. T.J.R. C.L.E. M.M.H. W.C.P. and B.A.T. are former employees of Deciphera Pharmaceuticals. L.C. is a former employee of Emerald Biostructures, which was a paid CRO of Deciphera Pharmaceuticals. A.M. A.T. and M.C.H. received financial support from Deciphera Pharmaceuticals for conduct of preclinical studies. F.J. A.R.A.R. and M.C.H. are principal investigators on the clinical study of ripretinib. F.J. and M.C.H. are on the Deciphera Clinical Advisory Board. M.C.H. has equity interest in MolecularMD, consults with MolecularMD, has provided expert testimony for Novartis, and consults with Blueprint Medicines. Deciphera Pharmaceuticals has patents on ripretinib and on its method of use. Funding Information: B.D.S., M.D.K., W.P.L., A.G., C.B.L., Y.M.A., G.A.A., S.L.B., T.M.C., R.R.S., Y.S., H.T., L.V., S.V., K.Y., and D.L.F. are employees and shareholders of Deciphera Pharmaceuticals. O.R. is an employee of Deciphera Pharmaceuticals. D.L.F. is founder of Deciphera Pharmaceuticals and a member of its scientific advisory board. S.C.W., T.J.R., C.L.E., M.M.H., W.C.P., and B.A.T. are former employees of Deciphera Pharmaceuticals. L.C. is a former employee of Emerald Biostructures, which was a paid CRO of Deciphera Pharmaceuticals. A.M., A.T., and M.C.H. received financial support from Deciphera Pharmaceuticals for conduct of preclinical studies. F.J., A.R.A.R., and M.C.H. are principal investigators on the clinical study of ripretinib. F.J. and M.C.H. are on the Deciphera Clinical Advisory Board. M.C.H. has equity interest in MolecularMD, consults with MolecularMD, has provided expert testimony for Novartis, and consults with Blueprint Medicines. Deciphera Pharmaceuticals has patents on ripretinib and on its method of use. Publisher Copyright: {\textcopyright} 2019 Elsevier Inc.",
year = "2019",
month = may,
day = "13",
doi = "10.1016/j.ccell.2019.04.006",
language = "English (US)",
volume = "35",
pages = "738--751.e9",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",
}