Selective Inhibitors of the Mutant B-Raf Pathway: Discovery of a Potent and Orally Bioavailable Aminoisoquinoline

Smith, Adrian L.; DeMorin, Frenel; Paras, Nick A.; Huang, Qi; Petkus, Jeffrey K.; Doherty, Elizabeth M.; Nixey, Thomas; Kim, Joseph L.; Whittington, Douglas A.; Epstein, Linda F.; Lee, Matthew R.; Rose, Mark J.; Babij, Carol; Fernando, Manory; Hess, Kristen L.; Le, Quynh Thu; Beltran, Pedro J.; Carnahan, Josette

doi:10.1021/jm901081g

Cited by 100 publications

(100 citation statements)

References 21 publications

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“…Here, we describe the biological activity of a novel series of potent Raf inhibitors (25). As expected and previously reported (18,20,21), cell lines and tumors harboring mutant B-Raf were sensitive to Raf inhibition.…”

Section: Discussionsupporting

confidence: 63%

“…2A-D), chosen based on its optimal potency and favorable pharmacokinetic properties (25). Tumor volume measurements over time are shown (Supplementary Table S2; Fig.…”

Section: Raf Inhibition Resulted In Tumor Growth Inhibition In Some Xmentioning

confidence: 99%

“…Earlyphase clinical studies of selective Raf inhibitors have shown objective clinical responses in some patients with tumors harboring V600E B-Raf (23,24). Here, we report on the in vitro and in vivo activity of a novel series of highly potent and selective Raf inhibitors (25) across a panel of cell and tumor xenograft models harboring MAPK pathway alterations as well as in normal cells and tissues. We show that MAPK pathway signal modulation correlates with cell, tumor, and normal tissue response to Raf inhibitors.…”

Section: Activating Mutations In Ras and Raf Occur In Tumorsmentioning

confidence: 99%

“…A description of the activity, selectivity, and syntheses of the full series of Raf inhibitors used here is presented elsewhere (25) Table S1). Dose-dependent downregulation of P-ERK by C-19 was confirmed by immunoblot (Fig.…”

Section: A Novel Series Of Kinase Inhibitors Showed Potent Biochemicamentioning

confidence: 99%

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Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Carnahan

Beltran

Babij

et al. 2010

Molecular Cancer Therapeutics

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Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations in B-Raf. Here, we show that cell lines and tumors harboring mutant B-Raf were sensitive to a novel series of Raf inhibitors (e.g., V600E B-Raf A375, IC 50 on cells = 2 nmol/L; ED 50 on tumor xenografts = 1.3 mg/kg). However, in cells and tumors with wild-type B-Raf, exposure to Raf inhibitors resulted in a dose-dependent and sustained activation of mitogen-activated protein kinase signaling. In some of these cell lines, Raf inhibition led to entry into the cell cycle, enhanced proliferation, and significantly stimulated tumor growth in vivo. Inhibition with structurally distinct Raf inhibitors or isoform-specific small interfering RNA knockdown of Raf showed that these effects were mediated directly through Raf. Either A-Raf or C-Raf mediated the Raf inhibitor-induced mitogen-activated protein kinase pathway activation in an inhibitor-specific manner. These paradoxical effects of Raf inhibition were seen in malignant and normal cells in vitro and in vivo. Hyperplasia of normal epithelial cells in the esophagus and the stomach was evident in mice with all efficacious Raf inhibitors (n = 8) tested. An implication of these results is that Raf inhibitors may induce unexpected normal cell and tumor tissue proliferation in patients. Mol Cancer Ther; 9(8); 2399-410. ©2010 AACR.

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Section: Discussionsupporting

confidence: 63%

“…2A-D), chosen based on its optimal potency and favorable pharmacokinetic properties (25). Tumor volume measurements over time are shown (Supplementary Table S2; Fig.…”

Section: Raf Inhibition Resulted In Tumor Growth Inhibition In Some Xmentioning

confidence: 99%

Section: Activating Mutations In Ras and Raf Occur In Tumorsmentioning

confidence: 99%

Section: A Novel Series Of Kinase Inhibitors Showed Potent Biochemicamentioning

confidence: 99%

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Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Carnahan

Beltran

Babij

et al. 2010

Molecular Cancer Therapeutics

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“…The atomic coordinates of the five complexes with V600E B-Raf were retrieved from the Protein Data Bank (PDB entries: 1UWJ [3], 3C4C [34], 3IDP [35], 3II5 [36], 3Q96 [237]). In the case of the 1UWJ and 3Q96 complexes, only one of the two asymmetrically packed kinase-inhibitor complexes of the crystallographic unit was selected for further studies.…”

Section: Preparation Of the Complexesmentioning

confidence: 99%

Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations

Coronel¹,

Granadino‐Roldán²,

Pinto³

et al. 2015

CAD

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Potassium tert‐Butoxide‐Promoted Synthesis of 1‐Aminoisoquinolines from 2‐Methylbenzonitriles and Benzonitriles under Catalyst‐Free Conditions

Feng

2016

Adv Synth Catal

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Selective Inhibitors of the Mutant B-Raf Pathway: Discovery of a Potent and Orally Bioavailable Aminoisoquinoline

Cited by 100 publications

References 21 publications

Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Selective and Potent Raf Inhibitors Paradoxically Stimulate Normal Cell Proliferation and Tumor Growth

Insight into the Binding of DFG-out Allosteric Inhibitors to B-Raf Kinase Using Molecular Dynamics and Free Energy Calculations

Potassium tert‐Butoxide‐Promoted Synthesis of 1‐Aminoisoquinolines from 2‐Methylbenzonitriles and Benzonitriles under Catalyst‐Free Conditions

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