Recent progress in the identification of BRAF inhibitors as anti-cancer agents

El‐Nassan, Hala B.

doi:10.1016/j.ejmech.2013.11.018

Cited by 57 publications

(30 citation statements)

References 137 publications

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“…Many Raf inhibitors have been developed recently . Besides sorafenib, the multikinase inhibitor Regorafenib (SCH66336) blocks BRAF, VEGFR‐2, VEGFR‐3, PDGFR‐b, c‐Kit, Flt3, RET and CSF‐1R .…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

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The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

Delire

Stärkel

2015

Eur J Clin Investigation

220

179

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Background Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50-100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications.

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Section: Therapeutic Implicationsmentioning

confidence: 99%

“…Specific B‐Raf inhibitors have also been discovered during the last decade. Many of them exhibit an antitumour activity only against tumours harbouring B‐Raf mutations such as melanoma .…”

Section: Therapeutic Implicationsmentioning

confidence: 99%

The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

Delire

Stärkel

2015

Eur J Clin Investigation

220

179

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“…In particular, RAS mutations occur in ≈15% of all cancers, and mutations in BRAF, but not its isoforms, are prevalent in melanomas (≈66%), thyroid cancer (up to 70%), ovarian cancer (≈30%), colorectal cancer (up to 20%), and liver cancer (≈14%) (El-Nassan, 2014). By far the most common oncogenic mutation occurs in the activation segment of BRAF, V600E, and is found in ≈90% of cancers linked to this kinase.…”

Section: Introductionmentioning

confidence: 99%

The RAS-Binding Domain of Human BRAF Protein Serine/Threonine Kinase Exhibits Allosteric Conformational Changes upon Binding HRAS

et al. 2015

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SUMMARY RAS binding is a critical step in the activation of BRAF protein serine/threonine kinase and stimulation of the mitogen-activated protein kinase signaling pathway. Mutations in both RAS and BRAF are associated with many human cancers. Here, we report the solution nuclear magnetic resonance (NMR) and X-ray crystal structures of the RAS-binding domain (RBD) from human BRAF. We further studied the complex between BRAF RBD and the GppNHp bound form of HRAS in solution. Backbone, side-chain, and 19F NMR chemical shift perturbations reveal unexpected changes distal to the RAS-binding face that extend through the core of the RBD structure. Moreover, backbone amide hydrogen/deuterium exchange NMR data demonstrate conformational ensemble changes in the RBD core structure upon complex formation. These changes in BRAF RBD reveal a basis for allosteric regulation of BRAF structure and function, and suggest a mechanism by which RAS binding can signal the drastic domain rearrangements required for activation of BRAF kinase.

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“…Pyridopyrazinone derivatives had considerable therapeutic activities in the treatment of different cancer types as melanoma, thyroid, colon, and ovarian cancer through their selective inhibition of V600E BRAF [21]. Pyridopyrazinone derivatives were considered type II inhibitors of V600E BRAF, both in vitro and in vivo.…”

Section: Introductmentioning

confidence: 99%

“…In additio r all synthesized blished with act molecular dockin r V600E BRAF kinas oid cancer. The n t C-3 or fused w and exhibited ma, ovarian, thyr 7(1), [19][20][21][22][23][24][25][26][27][28][29] The most com tations is V600E bstitution (val p) which is ad ring BRAF activ the phosphory dering V600E BRA wth [5,6,12 However, derivatives of pyrimidine, azaindole and benzimidazole such as darafenib, vemurafenib and RAF265, respectively, were involved in clinical trials as V600E BRAF kinase inhibitors [21] (Figure 1).…”

Section: Introductmentioning

confidence: 99%

Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone

et al. 2016

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Recent progress in the identification of BRAF inhibitors as anti-cancer agents

Cited by 57 publications

References 137 publications

The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications

The RAS-Binding Domain of Human BRAF Protein Serine/Threonine Kinase Exhibits Allosteric Conformational Changes upon Binding HRAS

Design, synthesis, anticancer evaluation and molecular docking of new V600EBRAF inhibitors derived from pyridopyrazinone

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