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

Rheault, Tara R.; Stellwagen, John; Adjabeng, George M.; Hornberger, Keith R.; Petrov, Kimberly G.; Waterson, Alex G.; Dickerson, Scott H.; Mook, Robert A.; Laquerre, Sylvie; King, Alastair J.; Rossanese, Olivia W.; Arnone, Marc R.; Smitheman, Kimberly N.; Kane-Carson, Laurie S.; Han, Chao; Moorthy, Ganesh S.; Moss, Katherine G.; Uehling, David

doi:10.1021/ml4000063

Cited by 209 publications

(184 citation statements)

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“…To identify potent inhibitors of dimeric BRAF, we compared eight structurally diverse RAF inhibitors: AZ-628 (AZ) (McDermott et al, 2007), TAK-632 (TAK) , LY3009120 (LY) (Peng et al, 2015), GDC-0879 (GDC) (Hoeflich et al, 2009), SB-590885 (SB) (King et al, 2006), PLX7904/Paradox Breaker (PB), which does not to induce paradoxical activation in wild-type BRAF cells , Vemurafenib (VEM) and Dabrafenib (DAB) (Rheault et al, 2013) (Figure S1A, Table S1). To compare potencies of inhibitors in cells endogenously expressing monomeric or dimeric BRAF V600E , we treated parental (PAR) SKMEL239 cells expressing full length BRAF V600E and the SKMEL239 derivative (clone C3) that is resistant to VEM due to enhanced dimerization of endogenous splice variants of BRAF V600E that lack the RAS-binding domain (Poulikakos et al, 2011).…”

Section: Structurally Diverse Raf Inhibitors Equi-potently Inhibit Momentioning

confidence: 99%

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Karoulia¹,

Wu²,

Ahmed³

et al. 2016

Cancer Cell

127

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SUMMARYThe complex biochemical effects of RAF inhibitors account for both the effectiveness and mechanisms of resistance to these drugs, but a unified mechanistic model has been lacking. HereCorrespondence and requests for materials should be addressed to: Poulikos.poulikakos@mssm.edu or evripidis.gavathiotis@einstein.yu.edu. * These authors contributed equally to this work Accession numbers. Structural coordinates and parameters have been submitted to the Protein Database Bank under the following accession codes: 4RZV for BRAF R509H /VEM, 4RZW for BRAF R509H /AZ and 5ITA for BRAF WT /AZ-VEM. Other structural coordinates used in this study are the following: PDB ID: 4KSP for TAK bound to BRAF dimer, PDB ID: 3OG7 for VEM bound to BRAF V600E dimer, PDB ID: 4MNF for GDC bound to BRAF V600E dimer, PDB ID: 2FB8 for SB bound to BRAF dimer, PDB ID: 4XV2 for DAB bound to BRAF V600E dimer and PDB ID: 4XV1 for PB bound to BRAF V600E dimer and PDB 4MNE for the BRAF/MEK complex. AUTHOR CONTRIBUTIONSP.I.P., E.G., C.K., M.H., A.L., Z.K., Y.W. and T.A.A designed experiments. Z.K., T.A.A conducted biochemical and cellular studies. E.G., Y.W. performed structural determination and structural analysis. X.W. generated the CRAF-V5 CRISPR cell line. Q.X. synthesized the AZ-VEM compound. C.K., M.H., J.A.F., A.L., E.G., P.I.P. designed animal studies. Z.K., T.A.A and J.B. conducted animal experiments. C.Z. and G.B. provided reagents and analyzed data. P.I.P. and E.G. designed research, analyzed data and wrote the manuscript, which was edited by all authors.C.Z. and G.B. are employees of Plexxikon Inc. All other authors declare no competing financial interests.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. we show that RAF inhibitors exert their effects via two distinct allosteric mechanisms. Drug resistance due to dimerization is determined by the position of the αC-helix stabilized by inhibitor, whereas inhibitor-induced RAF priming and dimerization are the result of inhibitor-induced formation of the RAF/RAS-GTP complex. The biochemical effect of RAF inhibitor in cells is the combined outcome of the two mechanisms. Therapeutic strategies including αC-helix-IN inhibitors are more effective in multiple mutant BRAF-driven tumor models, including colorectal and thyroid BRAF V600E cancers, in which first generation RAF inhibitors have been ineffective. HHS Public Access

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Section: Structurally Diverse Raf Inhibitors Equi-potently Inhibit Momentioning

confidence: 99%

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Karoulia¹,

Wu²,

Ahmed³

et al. 2016

Cancer Cell

127

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“…Taken together, these results provide a full understanding of dabrafenib disposition in humans. (Adams et al, 2009;Rheault et al, 2013). Chemicals and solvents of reagent or high-performance liquid chromatography (HPLC) grade were purchased from commercial sources.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

et al. 2013

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A phase I study was conducted to assess the metabolism and excretion of [ 14 C]dabrafenib (GSK2118436; N-{3-[5-(2-amino-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,6-difluorobenzene sulfonamide, methanesulfonate salt), a BRAF inhibitor, in four patients with BRAF V600 mutation-positive tumors after a single oral dose of 95 mg (80 mCi). Assessments included the following: 1) plasma concentrations of dabrafenib and metabolites using validated ultra-highperformance liquid chromatography-tandem mass spectrometry methods, 2) plasma and blood radioactivity, 3) urinary and fecal radioactivity, and 4) metabolite profiling. Results showed the mean total recovery of radioactivity was 93.8%, with the majority recovered in feces (71.1% of administered dose). Urinary excretion accounted for 22.7% of the dose, with no detection of parent drug in urine. Dabrafenib is metabolized primarily via oxidation of the t-butyl group to form hydroxy-dabrafenib. Hydroxy-dabrafenib undergoes further oxidation to carboxy-dabrafenib, which subsequently converts to desmethyl-dabrafenib via a pH-dependent decarboxylation. The half-lives for carboxy-and desmethyl-dabrafenib were longer than for parent and hydroxy-dabrafenib (18-20 vs. 5-6 hours). Based on area under the plasma concentration-time curve, dabrafenib, hydroxy-, carboxy-, and desmethyl-dabrafenib accounted for 11%, 8%, 54%, and 3% of the plasma radioactivity, respectively. These results demonstrate that the major route of elimination of dabrafenib is via oxidative metabolism (48% of the dose) and biliary excretion. Based on our understanding of the decarboxylation of carboxy-dabrafenib, a low pH-driven, nonenzymatic mechanism involving participation of the aryl nitrogen is proposed to allow prediction of metabolic oxidation and decarboxylation of drugs containing an aryl nitrogen positioned a to an alkyl (ethyl or t-butyl) side chain.

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“…These FDA-approved agents demonstrated significant clinical benefit for melanoma patients harboring BRAF V600 mutation (Flaherty et al, 2010;Chapman et al, 2011;Hauschild et al, 2012). In preclinical studies, vemurafenib and dabrafenib showed effective suppression of MEK1/2 and ERK1/2 signaling and significant growth inhibition in tumor models expressing BRAF V600E oncogene (Joseph et al, 2010;Yang et al, 2010;Rheault et al, 2013). In clinical trials, vemurafenib demonstrated complete or partial response in majority of patients with malignant BRAF V600E melanoma.…”

Section: Development Of Braf Inhibitorsmentioning

confidence: 99%

Co-targeting BRAF and cyclin dependent kinases 4/6 for BRAF mutant cancers

Yadav

Chen

Yue

et al. 2015

Pharmacology & Therapeutics

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

Cited by 209 publications

References 11 publications

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

An Integrated Model of RAF Inhibitor Action Predicts Inhibitor Activity against Oncogenic BRAF Signaling

Metabolism and Disposition of Oral Dabrafenib in Cancer Patients: Proposed Participation of Aryl Nitrogen in Carbon-Carbon Bond Cleavage via Decarboxylation following Enzymatic Oxidation

Co-targeting BRAF and cyclin dependent kinases 4/6 for BRAF mutant cancers

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