Discovery of Dabrafenib: A Selective Inhibitor of Raf Kinases with Antitumor Activity against B-Raf-Driven Tumors.

Autor:	Rheault TR; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Stellwagen JC; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Adjabeng GM; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Hornberger KR; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Petrov KG; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Waterson AG; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Dickerson SH; Computational and Structural Chemistry, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States., Mook RA Jr; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States., Laquerre SG; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., King AJ; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Rossanese OW; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Arnone MR; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Smitheman KN; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Kane-Carson LS; Platform Technology & Science, GlaxoSmithKline , Research Triangle Park, North Carolina 27709, United States., Han C; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Moorthy GS; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Moss KG; Oncology R&D Cancer Research, GlaxoSmithKline , Collegeville Road, Collegeville, Pennsylvania 19426, United States., Uehling DE; Oncology R&D Medicinal Chemistry, GlaxoSmithKline , Research Triangle Park , North Carolina 27709, United States.
Jazyk:	angličtina
Zdroj:	ACS medicinal chemistry letters [ACS Med Chem Lett] 2013 Feb 07; Vol. 4 (3), pp. 358-62. Date of Electronic Publication: 2013 Feb 07 (Print Publication: 2013).
DOI:	10.1021/ml4000063
Abstrakt:	Hyperactive signaling of the MAP kinase pathway resulting from the constitutively active B-Raf(V600E) mutated enzyme has been observed in a number of human tumors, including melanomas. Herein we report the discovery and biological evaluation of GSK2118436, a selective inhibitor of Raf kinases with potent in vitro activity in oncogenic B-Raf-driven melanoma and colorectal carcinoma cells and robust in vivo antitumor and pharmacodynamic activity in mouse models of B-Raf(V600E) human melanoma. GSK2118436 was identified as a development candidate, and early clinical results have shown significant activity in patients with B-Raf mutant melanoma.
Databáze:	MEDLINE
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