Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class. - 0 views

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  #1 Donovan Kennedy on 28 Feb 12

   

  Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class, which has been discovered by Genentech Inc with a collaboration with Curis Inc. Vismodegib inhibits the Hedgehog (Hh) walkway, which is involved in tumorigenesis, thus providing a strong rationale due to the use in dealing a variety of malignancies. Vismodegib suppresses Hh signaling just by binding to and interfering with smoothened, a membrane protein that can offer positive signals to that Hh signaling pathway. Preclinical studies demonstrated that antitumor activity of vismodegib in mouse types of medulloblastoma (MB) and in xenograft types of colorectal and pancreatic cancer. Phase I clinical trials in patients with advanced basal cell carcinoma (BCC) and MB highlighted a target response to vismodegib. Reported adverse reactions were minor, with merely one grade 4 adverse occurrence. Vismodegib is currently undergoing phase II clinical trials for the treatment of advanced BCC, metastatic colorectal cancer, ovarian cancer, MB and also other solid tumors. Because of its small toxicity and specificity for any Hh pathway, this drug has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.r788,Afatinib,Vismodegib
  Boehringer Ingelheim announced promising results from two scientific trials of its investigational melanoma compound afatinib (BIBW 2992) presented at the 35 th European Society for Medical Oncology (ESMO) Our lawmakers in Milan, Italy. Results in the "LUX-Lung 1" trial suggest that afatinib (BIBW 2992) is highly active in late-stage patients with NSCLC1, while inside LUX-Lung 2 phase II trial afatinib demonstrated encouraging action in advanced NSCLC patients which happen to have a mutated EGF Receptor. Afatinib, that's taken as a tablet, is a next generation inhibitor with the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinase (TK) together with unlike first generation TKIs irreversibly binds to EGFR/HER2. The compound is under development in just a few solid tumour types. The LUX-Lung 1 trial (phase II b/III) compared afatinib to placebo within over 580 patients using advanced NSCLC whose disease has progressed after receiving chemotherapy and then a first-generation EGFR Tyrosine Kinase Inhibitor (gefitinib or even erlotinib)
  Inhibition of antigen-dependent B-cell receptor (BCR) signaling is believed a promising therapeutic strategy in CLL, but experimental in vivo evidence to support this view is nevertheless lacking. We have now investigated whether inhibition of BCR signaling along with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop inside Eμ-TCL1 transgenic mouse model of CLL. Similar to human CLL these leukemias express stereotyped BCRs which react with autoantigens exposed on the surface of senescent or apoptotic skin cells, suggesting that they are generally antigen-driven. We show that will R788 effectively inhibits BCR signaling within vivo, resulting in reduced proliferation and survival of the malignant B-cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs regardless of the odd relatively modest cytotoxic effect in vitro and it is independent of basal Syk action, suggesting that R788 options primarily by inhibiting antigen-dependent BCR signs. Importantly, the effect of R788 was found to remain selective for the cancerous clones, as no disturbance in the production of normal B-lymphocytes has been observed. Collectively, these data provide additionally rationale for clinical trials with R788 in CLL together with establish the BCR signaling pathway as an important therapeutic target from this disease.

   

  <div class="cArrow"> </div><div class="cContentInner">Vismodegib (GDC-0449) is a small, orally administrable molecule, belonging to the 2-arylpyridine class, which has been discovered by Genentech Inc with a collaboration with Curis Inc. Vismodegib inhibits the Hedgehog (Hh) walkway, which is involved in tumorigenesis, thus providing a strong rationale due to the use in dealing a variety of malignancies. Vismodegib suppresses Hh signaling just by binding to and interfering with smoothened, a membrane protein that can offer positive signals to that Hh signaling pathway. Preclinical studies demonstrated that antitumor activity of vismodegib in mouse types of medulloblastoma (MB) and in xenograft types of colorectal and pancreatic cancer. Phase I clinical trials in patients with advanced basal cell carcinoma (BCC) and MB highlighted a target response to vismodegib. Reported adverse reactions were minor, with merely one grade 4 adverse occurrence. Vismodegib is currently undergoing phase II clinical trials for the treatment of advanced BCC, metastatic colorectal cancer, ovarian cancer, MB and also other solid tumors. Because of its small toxicity and specificity for any Hh pathway, this drug has potential advantages compared with conventional chemotherapy, and may also be used in combination treatments. Clinical trials with other Hh inhibitors are also ongoing and their therapeutic potential will need to be compared with vismodegib.<a href="http://www.selleckchem.com/products/R7935788-Fostamatinib.html" rel="nofollow">r788</a>,<a href="http://www.selleckchem.com/products/BIBW2992.html" rel="nofollow">Afatinib</a>,<a href="http://www.selleckchem.com/products/GDC-0449.html" rel="nofollow">Vismodegib</a><br />Boehringer Ingelheim announced promising results from two scientific trials of its investigational melanoma compound afatinib (BIBW 2992) presented at the 35 th European Society for Medical Oncology (ESMO) Our lawmakers in Milan, Italy. Results in the "LUX-Lung 1" trial suggest that afatinib (BIBW 2992) is highly active in late-stage patients with NSCLC1, while inside LUX-Lung 2 phase II trial afatinib demonstrated encouraging action in advanced NSCLC patients which happen to have a mutated EGF Receptor. Afatinib, that's taken as a tablet, is a next generation inhibitor with the epidermal growth factor receptor (EGFR) and human epidermal receptor 2 (HER2) tyrosine kinase (TK) together with unlike first generation TKIs irreversibly binds to EGFR/HER2. The compound is under development in just a few solid tumour types. The LUX-Lung 1 trial (phase II b/III) compared afatinib to placebo within over 580 patients using advanced NSCLC whose disease has progressed after receiving chemotherapy and then a first-generation EGFR Tyrosine Kinase Inhibitor (gefitinib or even erlotinib)<br />Inhibition of antigen-dependent B-cell receptor (BCR) signaling is believed a promising therapeutic strategy in CLL, but experimental in vivo evidence to support this view is nevertheless lacking. We have now investigated whether inhibition of BCR signaling along with the selective Syk inhibitor fostamatinib disodium (R788) will affect the growth of the leukemias that develop inside Eμ-TCL1 transgenic mouse model of CLL. Similar to human CLL these leukemias express stereotyped BCRs which react with autoantigens exposed on the surface of senescent or apoptotic skin cells, suggesting that they are generally antigen-driven. We show that will R788 effectively inhibits BCR signaling within vivo, resulting in reduced proliferation and survival of the malignant B-cells and significantly prolonged survival of the treated animals. The growth-inhibitory effect of R788 occurs regardless of the odd relatively modest cytotoxic effect in vitro and it is independent of basal Syk action, suggesting that R788 options primarily by inhibiting antigen-dependent BCR signs. Importantly, the effect of R788 was found to remain selective for the cancerous clones, as no disturbance in the production of normal B-lymphocytes has been observed. Collectively, these data provide additionally rationale for clinical trials with R788 in CLL together with establish the BCR signaling pathway as an important therapeutic target from this disease.</div>

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