Design and Discovery of Small Molecules Targeting Raf-1 Kinase

Lowinger, Timothy B.; Riedl, Bernd; Dumas, Jacques; Smith, Roger A.

doi:10.2174/1381612023393125

Cited by 151 publications

(105 citation statements)

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“…In histopathological studies of skin toxicity associated with sorafenib in humans, the most relevant findings included keratinocyte vacuolar degeneration, the presence of intracytoplasmic eosinophilic bodies, and intraepidermal blisters in the stratum malpighii (Yang et al 2008). Sorafenib is a multi-kinase inhibitor initially developed to inhibit the Raf1 kinase pathway (Smith et al 2001;Lowinger et al 2002). In addition to inhibiting tumor-cell proliferation by targeting the Raf/MEK/ERK signaling pathway, sorafenib also inhibits angiogenesis by targeting tyrosine kinases such as vascular-endothelial growth factor receptor (VEGFR-2 and VEGFR-3), plateletderived growth factor receptor (PDGFR), Fms-like tyrosine kinase (FLT)-3, and c-KIT (Gollob 2005;Carlomagno et al 2006;Liu et al 2006;Wilhelm et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Shimada

Okawa

Kondo

et al. 2015

Tohoku J. Exp. Med.

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Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC sorafenib and AUC N-oxide , respectively). Inter-group comparison revealed that AUC N-oxide and AUC ratio (AUC N-oxide /AUC sorafenib ) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC N-oxide and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC N-oxide : 2.0 μg•day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC N-oxide ≤ 2.0 μg•day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

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Section: Discussionmentioning

confidence: 99%

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Shimada

Okawa

Kondo

et al. 2015

Tohoku J. Exp. Med.

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“…BAY 43-9006 is a novel investigational cancer therapeutic that potently inhibits the serine/threonine kinases RAF-1 and wildtype and V600E mutant BRAF, as well as several receptor tyrosine kinases (Lyons et al, 2001;Lowinger et al, 2002;Karasarides et al, 2004;Wilhelm et al, 2004). Similarly, studies of several small molecule RET inhibitors such as RPI-1 (Cuccuru et al, 2004), PP2 (Carlomagno et al, 2003) and ZD6474 (Carlomagno et al, 2002) suggest that RET oncoproteins are valid therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

et al. 2005

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Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutationspecific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.

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“…This compound, originally identified in a screen for Raf kinase inhibitors, has been shown to effectively inhibit the activity of wild-type B-Raf protein (31,32). Initially, we determined the concentration of BAY 43-9006 that reduced UACC 903 cell survival by half, also called the IC 50 , and found it to be 5 to 6 Amol/L (data not shown).…”

Section: Sirna-mediated Targeting Of Mutantmentioning

confidence: 99%

Mutant V599EB-Raf Regulates Growth and Vascular Development of Malignant Melanoma Tumors

et al. 2005

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Activating mutations of the B-RAF gene are observed in >60% of human melanomas. Approximately 90% of these mutations occur in the activation segment of the kinase domain as a single-base substitution that converts a valine to glutamic acid at codon 599 (V599E) in exon 15. This mutation causes activation of the kinase as well as downstream effectors of the mitogen-activated protein kinase-signaling cascade, leading to melanoma tumor development by an as yet unknown mechanism. In this study, we have identified the role of V599E BRaf in melanoma tumor development by characterizing the mechanism by which this mutant protein promotes melanoma tumorigenesis. Small interfering RNA targeted against B-Raf or a Raf kinase inhibitor (BAY 43-9006) was used to reduce expression and/or activity of V599E B-Raf in melanoma tumors. This inhibition led to reduced activity of the mitogenactivated protein kinase-signaling cascade and inhibited tumor development in animals. Targeted reduction of mutant V599E B-Raf expression (activity) in melanoma cells before tumor formation inhibited tumorigenesis by reducing the growth potential of melanoma cells. In contrast, reduction of mutant V599E B-Raf activity in preexisting tumors prevented further vascular development mediated through decreased vascular endothelial growth factor secretion, subsequently increasing apoptosis in tumors. These effects in combination with reduced proliferative capacity halted growth, but did not shrink the size of preexisting melanoma tumors. Thus, these studies identify the mechanistic underpinnings by which mutant V599E B-RAF promotes melanoma development and show the effectiveness of targeting this protein to inhibit melanoma tumor growth. (Cancer Res 2005; 65(6): 2412-21)

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Design and Discovery of Small Molecules Targeting Raf-1 Kinase

Cited by 151 publications

References 0 publications

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Monitoring Serum Levels of Sorafenib and Its <i>N</i>-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

Mutant V599EB-Raf Regulates Growth and Vascular Development of Malignant Melanoma Tumors

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