ACS Medicinal Chemistry Letters
Letter
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from a phase I/II study of the oral BRAF inhibitor dabrafenib
(GSK2118436) combined with the oral MEK 1/2 inhibitor trametinib
(GSK1120212) in patients with BRAFi-naive metastatic melanoma.
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(5) Wan, P.; Garnett, M.; Roe, S.; Lee, S.; Niculescu-Duvaz, D.;
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(9) Efforts were focused on optimizing pharmacokinetic properties in
rat and dog to identify two species for preclinical safety studies.
(10) Previously, we reported that fluorination of the arylsulfonamide
headgroup at the 2-, 3-, 2,5-, and 2,6-positions gave optimal, and nearly
interchangeable, potency in this series. Additionally, in vivo
pharmacokinetic studies in rat and dog with similarly paired analogues
showed that changes in the headgroup substitution pattern had little
impact on either clearance or oral absorption. Thus, potency and
pharmacokinetic properties observed in this series do not appear to be
sensitive to changes in the fluorination pattern of the headgroup. See
ref 8.
(11) For a discussion of the binding efficiency of truncated tail-
containing molecule 2 compared to 1 in the context of the B-Raf
binding mode, see the Supporting Information.
(12) For a thorough biological characterization of dabrafenib, see:
King, A.; Arnone, M.; Bleam, M.; Moss, K.; Yang, J.; Fisher, K.;
Smitheman, K.; Erhardt, J.; Hughes-Earle, A.; Kane-Carson, L.;
Sinnamon, R.; Qi, H.; Rheault, T.; Uehling, D.; Laquerre, S. Novel
Selective BRAF Inhibitor (GSK2118436; dabrafenib) with Demon-
stration of Increased Efficacy and Reduced Skin Lesions by Combining
BRAF and MEK Inhibitors. Manuscript in preparation.
(13) Broader kinase profiling was recently conducted on a set of 270
kinases (Millipore), and <100-fold activity was observed for only
LIMK1, NEK11, PKD2, and SIK in addition to ALK5. See ref 12.
(14) Gellibert, F.; de Gouville, A.-C.; Woolven, J.; Mathews, N.;
Nguyen, V.-L.; Bertho-Ruault, C.; Patikis, A.; Grygielko, E.; Laping,
N.; Huet, S. Discovery of 4-{4-[3-(Pyridin-2-yl)-1H-pyrazol-4-yl]-
pyridin-2-yl}-N-(tetrahydro-2H-pyran-4-yl)benzamide (GW788388):
A Potent, Selective, and Orally Active Transforming Growth Factor-
β Type I Receptor Inhibitor. J. Med. Chem. 2006, 49, 2210−2221.
(15) Hauschild, A.; Grob, J.; Demidov, L.; Jouary, T.; Gutzmer, R.;
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Martin, A.; Swann, S.; Haney, P.; Mirakhur, B.; Guckert, M.;
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dx.doi.org/10.1021/ml4000063 | ACS Med. Chem. Lett. XXXX, XXX, XXX−XXX