Sorafenib: a clinical and pharmacologic review

Iyer, Renuka; Fetterly, Gerald J.; Lugade, Amit A.; Thanavala, Yasmin

doi:10.1517/14656566.2010.496453

Cited by 142 publications

(104 citation statements)

References 49 publications

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“…Pharmacological approaches to studying protein kinases can be challenging to implement because it is difficult to generate selective ATP-competitive inhibitors. In several serendipitous cases, an originally unwanted "off target" of a kinase inhibitor in the clinic turned out to drive therapeutic efficacy while the original target was irrelevant (5,6).…”

Section: Chemical Genetics | Irreversible Inhibitor | Sgk494mentioning

confidence: 99%

Chemical genetic strategy for targeting protein kinases based on covalent complementarity

Garske

Peters

Cortesi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The conserved nature of the ATP-binding site of the >500 human kinases renders the development of specific inhibitors a challenging task. A widely used chemical genetic strategy to overcome the specificity challenge exploits a large-to-small mutation of the gatekeeper residue (a conserved hydrophobic amino acid) and the use of a bulky inhibitor to achieve specificity via shape complementarity. However, in a number of cases, introduction of a glycine or alanine gatekeeper results in diminished kinase activity and ATP affinity. A new chemical genetic approach based on covalent complementarity between an engineered gatekeeper cysteine and an electrophilic inhibitor was developed to address these challenges. This strategy was evaluated with Src, a proto-oncogenic tyrosine kinase known to lose some enzymatic activity using the shape complementarity chemical genetic strategy. We found that Src with a cysteine gatekeeper recapitulates wild type activity and can be irreversibly inhibited both in vitro and in cells. A cocrystal structure of T338C c-Src with a vinylsulfonamide-derivatized pyrazolopyrimidine inhibitor was solved to elucidate the inhibitor binding mode. A panel of electrophilic inhibitors was analyzed against 307 kinases and MOK (MAPK/MAK/MRK overlapping kinase), one of only two human kinases known to have an endogenous cysteine gatekeeper. This analysis revealed remarkably few offtargets, making these compounds the most selective chemical genetic inhibitors reported to date. Protein engineering studies demonstrated that it is possible to increase inhibitor potency through secondary-site mutations. These results suggest that chemical genetic strategies based on covalent complementarity should be widely applicable to the study of protein kinases. chemical genetics | irreversible inhibitor | SgK494

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Section: Chemical Genetics | Irreversible Inhibitor | Sgk494mentioning

confidence: 99%

Chemical genetic strategy for targeting protein kinases based on covalent complementarity

Garske

Peters

Cortesi

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Sorafenib causes apoptosis in leukemia cell lines and in blast cells from patients with acute myeloid leukemia (10) and displays a broad-spectrum antitumor activity in colon, breast and non-small-cell lung cancer xenograft models (11). Sorafenib was approved by the U.S. Food and Drug Administration for the treatment of patients with advanced renal cell carcinoma and unresectable hepatocellular carcinoma (12). As the first drug to improve the survival of patients with hepatocellular carcinoma, sorafenib is currently being tested in clinical trials for its efficacy in the treatment of other solid tumors such as thyroid carcinoma (12).…”

Section: Sorafenib-induced Apoptosis Of Chronic Lymphocytic Leukemia mentioning

confidence: 99%

Sorafenib-Induced Apoptosis of Chronic Lymphocytic Leukemia Cells Is Associated with Downregulation of RAF and Myeloid Cell Leukemia Sequence 1 (Mcl-1)

Fecteau

Bharati

O’Hayre

et al. 2011

Mol Med

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We have previously shown that sorafenib, a multikinase inhibitor, exhibits cytotoxic effects on chronic lymphocytic leukemia (CLL) cells. Because the cellular microenvironment can protect CLL cells from drug-induced apoptosis, it is important to evaluate the effect of novel drugs in this context. Here we characterized the in vitro cytotoxic effects of sorafenib on CLL cells and the underlying mechanism in the presence of marrow stromal cells (MSCs) and nurselike cells (NLCs). One single dose of 10 μmol/L or the repeated addition of 1 μmol/L sorafenib caused caspase-dependent apoptosis and reduced levels of phosphorylated B-RAF, C-RAF, extracellular signal-regulated kinase (ERK), signal transducer and activator of transcription 3 (STAT3) and myeloid cell leukemia sequence 1 (Mcl-1) in CLL cells in the presence of the microenvironment. We show that the RAF/mitogen-activated protein kinase kinase (MEK)/ERK pathway can modulate Mcl-1 expression and contribute to CLL cell viability, thereby associating sorafenib cytotoxicity to its impact on RAF and Mcl-1. To evaluate if the other targets of sorafenib can affect CLL cell viability and contribute to sorafenib-mediated cytotoxicity, we tested the sensitivity of CLL cells to several kinase inhibitors specific for these targets. Our data show that RAF and vascular endothelial growth factor receptor (VEGFR) but not KIT, platelet-derived growth factor receptor (PDGFR) and FMS-like tyrosine kinase 3 (FLT3) are critical for CLL cell viability. Taken together, our data suggest that sorafenib exerts its cytotoxic effect likely via inhibition of the VEGFR and RAF/MEK/ERK pathways, both of which can modulate Mcl-1 expression in CLL cells. Furthermore, sorafenib induced apoptosis of CLL cells from fludarabine refractory patients in the presence of NLCs or MSCs. Our results warrant further clinical exploration of sorafenib in CLL.

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“…PTK inhibitors with broad-spectrum specificity are increasingly expected to demonstrate a better clinical benefit than selective agents [26] . Some multi-targeted PTK inhibitors approved by the FDA/ EMEA, such as sorafenib [27] and sunitinib [28] , are marked as a new generation of PTK inhibitor drugs. We have previously reported that hematoxylin is a multi-targeted inhibitor of several tyrosine kinases, including c-Src, c-Met, FGFR1, EGFR, VEGFR, PDGFR, and c-Kit [29] .…”

Section: Discussionmentioning

confidence: 99%

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

et al. 2011

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Aim: The insulin-like growth factor-1 receptor (IGF1R) is over-expressed in a wide variety of tumors and contributes to tumor cell proliferation, metastasis and drug resistance. The aim of this study was to establish a sensitive screening platform to identify novel IGF1R inhibitors. Methods: The catalytic domain of IGF1R was expressed using the Bac-to-Bac baculovirus expression system. The screening platform for IGF1R inhibitors was established based on ELISA. The binding profile of IGF1R with the inhibitors was predicted with molecular docking and then subjected to the surface plasmon resonance (SPR) approach. The growth inhibition of cancer cells by the inhibitors was assessed with MTT assay. Apoptosis was analyzed using flow cytometry and Western blotting. Results: A naturally occurring small molecule compound hematoxylin was identified as the most potent inhibitor (IC 50 value=1.8±0.1 μmol/L) within a library of more than 200 compounds tested. Molecular simulation predicted the possible binding mode of hematoxylin with IGF1R. An SPR assay further confirmed that hematoxylin bound directly to IGF1R with high binding affinity (Kd=4.2×10 -6 mol/L). In HL-60 cancer cells, hematoxylin inactivated the phosphorylation of IGF1R and downstream signaling and therefore suppressed cell proliferation. Mechanistic studies revealed that hematoxylin induced apoptosis in HL-60 cells via both extrinsic and intrinsic pathways. Conclusion: A simple, sensitive ELISA-based screening platform for identifying IGF1R inhibitors was established. Hematoxylin was identified as a promising IGF1R inhibitor with effective antitumor activity that deserves further investigation.

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Sorafenib: a clinical and pharmacologic review

Abstract: Sorafenib is a well-tolerated oral antiangiogenic agent approved for treatment of two angiogenesis-driven cancers. Studies to broaden the clinical indications and increase understanding of the clinical and laboratory biomarkers of response are needed.

Cited by 142 publications

References 49 publications

Chemical genetic strategy for targeting protein kinases based on covalent complementarity

Chemical genetic strategy for targeting protein kinases based on covalent complementarity

Sorafenib-Induced Apoptosis of Chronic Lymphocytic Leukemia Cells Is Associated with Downregulation of RAF and Myeloid Cell Leukemia Sequence 1 (Mcl-1)

Establishment of platform for screening insulin-like growth factor-1 receptor inhibitors and evaluation of novel inhibitors

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