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Dovitinib

The orally bioavailable lactate salt of a benzimidazole-quinolinone compound with potential antineoplastic activity. Dovitinib strongly binds to fibroblast growth factor receptor 3 (FGFR3) and inhibits its phosphorylation, which may result in the inhibition of tumor cell proliferation and the induction of tumor cell death. In addition, this agent may inhibit other members of the RTK superfamily, including the vascular endothelial growth factor receptor; fibroblast growth factor receptor 1; platelet-derived growth factor receptor type 3; FMS-like tyrosine kinase 3; stem cell factor receptor (c-KIT); and colony-stimulating factor receptor 1; this may result in an additional reduction in cellular proliferation and angiogenesis, and the induction of tumor cell apoptosis. The activation of FGFR3 is associated with cell proliferation and survival in certain cancer cell types. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Background An unmet medical need exists for patients with metastatic renal cell carcinoma who have progressed on VEGF-targeted and mTOR-inhibitor therapies. Fibroblast growth factor (FGF) pathway activation has been proposed as a mechanism of escape from VEGF-targeted therapies. Dovitinib is an oral tyrosine-kinase inhibitor that inhibits VEGF and FGF receptors. We therefore compared dovitinib with sorafenib as third-line targeted therapies in patients with metastatic renal cell carcinoma.Dovitinib showed activity, but this was no better than that of sorafenib in patients with renal cell carcinoma who had progressed on previous VEGF-targeted therapies and mTOR inhibitors. This trial provides reference outcome data for future studies of targeted inhibitors in the third-line setting.

Dovitinib failed to meet the primary endpoint of improving progression-free survival (PFS) versus sorafenib (Nexavar) in patients with heavily pretreated progressive renal cell carcinoma (RCC), according to phase III interim data reported at the 2013 European Cancer Congress (ECC). All patients had received prior treatment with both a VEGF- and an mTOR-targeted therapy. “These outcome data highlight the need for more effective drugs for RCC. There is an unmet need for treatment of RCC patients who progress after treatment with VEGF targeted therapies and mTOR inhibitors,” said lead author Robert Motzer, MD, Memorial Sloan-Kettering Cancer Center (MSKCC), New York City. A few positive aspects for researchers were that dovitinib did have acceptable tolerability, and the study will provide landmark PFS and overall survival (OS) data for future studies of third-line agents in RCC. - See more at: http://www.onclive.com/conference-coverage/ecco-esmo-2013/Dovitinib-Fails-as-Third-Line-Option-in-Kidney-Cancer#sthash.SADsCeXM.dpuf

Varlitinib

An orally bioavailable inhibitor of the epidermal growth factor receptor family with potential antineoplastic activity. Varlitinib selectively and reversibly binds to both EGFR (ErbB-1) and Her-2/neu (ErbB-2) and prevents their phosphorylation and activation, which may result in inhibition of the associated signal transduction pathways, inhibition of cellular proliferation and cell death. EGFR and Her-2 play important roles in cell proliferation and differentiation and are upregulated in various human tumor cell types. Due to the dual inhibition of both EGFR and Her-2, this agent may be therapeutically more effective than agents that inhibit EGFR or Her-2 alone. Check for active clinical trials or closed clinical trials using this agent. (NCI Thesaurus)

Salirasib

The Ras inhibitor farnesylthiosalicylic acid (Salirasib) disrupts the spatiotemporal localization of active Ras: a potential treatment for cancer.

Chronic activation of Ras proteins by mutational activation or by growth factor stimulation is a common occurrence in many human cancers and was shown to induce and be required for tumor growth. Even if additional genetic defects are present, "correction" of the Ras defect has been shown to reverse Ras-dependent tumorigenesis. One way to block Ras protein activity is by interfering with their spatiotemporal localization in cellular membranes or in membrane microdomains, a prerequisite for Ras signaling and biological activity. Detailed reports describe the use of this method in studies employing farnesylthiosalicylic acid (FTS, Salirasib), a Ras farnesylcysteine mimetic, which selectively disrupts the association of chronically active Ras proteins with the plasma membrane. FTS competes with Ras for binding to Ras-escort proteins, which possess putative farnesyl-binding domains and interact only with the activated form of Ras proteins, thereby promoting Ras nanoclusterization in the plasma membrane and robust signals. This chapter presents three-dimensional time-lapse images that track the FTS-induced inhibition of membrane-activated Ras in live cells on a real-time scale. It also describes a mechanistic model that explains FTS selectivity toward activated Ras. Selective blocking of activated Ras proteins results in the inhibition of Ras transformation in vitro and in animal models, with no accompanying toxicity. Phase I clinical trials have demonstrated a safe profile for oral FTS, with minimal side effects and promising activity in hematological malignancies. Salirasib is currently undergoing trials in patients with pancreatic cancer and with nonsmall cell lung cancer, with or without identified K-Ras mutations. The findings might indicate whether with the disruption of the spatiotemporal localization of oncogenic Ras proteins and the targeting of prenyl-binding domains by anticancer drugs is worth developing as a means of cancer treatment.

A phase II trial of Salirasib in patients with lung adenocarcinomas with KRAS mutations.

INTRODUCTION: KRAS mutations are present in 30% of lung adenocarcinomas. Salirasib prevents Ras membrane binding thereby blocking the function of all Ras isoforms. This phase II study determined the activity of salirasib in patients with advanced lung adenocarcinomas with KRAS mutations. METHODS: Two cohorts of patients with stage IIIB/IV lung adenocarcinoma were eligible: patients with tumors with KRAS mutations who were previously treated with chemotherapy and patients receiving initial therapy who had ≥15 pack-year smoking history. Salirasib was given orally from days 1 to 28 of a 35-day cycle. The primary end point was the rate of nonprogression at 10 weeks. RESULTS: Thirty-three patients were enrolled. Thirty patients had KRAS mutations (23 patients who were previously treated and 7/10 patients who had no prior therapy). Of the previously treated patients, 7 of 23 (30%) had stable disease at 10 weeks, and 4 of 10 (40%) previously untreated patients had stable disease at 10 weeks. No patient had a radiographic partial response (0% observed rate, 95% confidence interval 0-12%). The median overall survival was not reached (>9 months) for previously untreated patients and it was 15 months for patients who received prior chemotherapy. Diarrhea, nausea, and fatigue were the most common toxicities. CONCLUSIONS: Salirasib at the current dose and schedule has insufficient activity in the treatment of KRAS mutant lung adenocarcinoma to warrant further evaluation. The successful enrollment of 30 patients with tumors with KRAS mutant lung adenocarcinoma over 15 months at a single site demonstrates that drug trials directed at a KRAS-specific genotype in lung cancer are feasible.

Bevasiranib

As far as possible and common, are SI units used. Unless noted otherwise, data are given for at standard conditions . Bevasiranib is currently undergoing clinical development phase biological agent . It is chemically a so-called siRNA and one of the first products tested on patients of this group of drugs. Bevasiranib acts through a closure of the gene for vascular endothelial growth factor (VEGF) by RNA interference . It is potentially a drug in the treatment of age-related macular degeneration are used. Bevasiranib was developed by the pharmaceutical company OPKO developed.

Bevasiranib different than a conventional siRNA of low molecular weight and proteinaceous drugs. It makes use of the cell's own mechanism of RNA interference advantage and inhibits the activation of the VEGF gene. As a result, less VEGF is protein formed administration. Unlike other VEGF inhibitors, such as bevacizumab and ranibizumab , Bevasiranib not directly blocked the growth factor protein. Thus Bevasiranib has no immediate effect, as only existing VEGF has to be reduced.

In animal experiments, Bevasiranib inhibits responsible for age-related macular degeneration neovascularization of the network and choroid of the eye. [3]

Uptake and distribution in the body (pharmacokinetics) [ edit ] After an intravitreal injection into the vitreous body of the eye Bevasiranib distributed in animal experiments in the iris , the sclera , and particularly in the retina. The highest concentration is achieved in the target tissues after 24 to 72 hours. The half-life in the eye is between 50 and 80 hours. [4]

History [ Edit ] Bevasiranib was the first siRNA to patients in clinical trials has been tested in Phase III. The first Phase III trial, called the COBALT study ( Co mbining- B evasiranib- A nd- L ucentis- T herapy study) was canceled, [5] after it became clear that the study objective can not be achieved. Further clinical Phase III studies with other regimens are in preparation.

References [ Edit ] 1. ↑ jump up by: a b c World Health Organization: International Nonproprietary Names for Pharmaceutical Substances (INN) - Recommended International Nonproprietary Names: List 61 . In: WHO Drug Information . 23, no. 1 of 2009. 2. Jumping Up ↑ This substance has not yet been rated on their dangerousness either in terms of which a reliable and quotable source for this purpose has not been found. 3. Jumping Up ↑ Empire SJ, Fosnot J, Kuroki A, et al. : Small interfering RNA (siRNA) targeting VEGF Effectively Inhibits ocular neovascularization in a mouse model . In: Mol. Vis. . 9, May 2003, pp 210–216. PMID 12789138 . 4. Jumping Up ↑ Dejneka NS, Wan S, Bond OS, grain breast DJ, SJ Empire: Ocular biodistribution of a single intravitreal injection Following bevasiranib to rabbit eyes . In: Mol. . Vis . 14, 2008, pp 997–1005. PMID 18523657 . PMC : 2,405,815 (free full text). 5. Jumping Up ↑ ClinicalTrials.gov: Safety & Efficacy Study Evaluating the Combination of Bevasiranib & Lucentis Therapy in Wet AMD (COBALT) . Retrieved on November 7 of 2010.

Bafetinib

Bafetinib , previously as INNO-406 , NS-187 and CNS-9 refers is an experimental drug from the substance group of benzamides , who as Tyrosinkinasehemmstoff to be used. [2] It was originally developed by the Japanese company Nippon Shinyaku and 2006 Innovive Pharmaceuticals licensed. [3] Innovive was established in June 2008 by the CytRx Corp. adopted. [4]

Pharmacology [ Edit ] Bafetinib is an inhibitor of tyrosine kinases . It affects the formation of the fusion protein Bcr-Abl , as well as that of the enzyme Lyn kinase and should in mice ten times stronger effect than the imported Tyrosinkinasehemmstoff imatinib . [5]

Clinical Development [ Edit ] Bafetinib currently has no indication for an authorization as medicines .

The drug is intended for the treatment of chronic lymphocytic leukemia are developed (CLL). For this indication is Bafetinib is in the development phase II (June 2011). [6]

Bafetinib is also in phase II for the treatment of hormone-refractory prostate cancer . [7]

The US regulatory authority FDA had Bafetinib end of 2006, the status of a drug orphan (orphan drug) awarded. [8] This status could allow an accelerated development and approval.

References [ Edit ] 1. Jumping Up ↑ This substance has not yet been rated on their dangerousness either in terms of which a reliable and quotable source for this purpose has not been found. 2. Jumping Up ↑ A. Quintas-Cardama include: Flying under the radar: the new wave of BCR-ABL inhibitors. In: Nature Reviews Drug Discovery 6/2007, pp 834–848, PMID 17853901 . 3. Jumping Up ↑ Nippon Shinyaku. press release dated January 5, 2006 (s.) , accessed on 25 February 2011th 4. Jumping Up ↑ Drugs.com: Signs Definitive Agreement Cytrx Corporation to Acquire Innovive Pharmaceuticals, Inc. Retrieved June 17, 2011 5. Jumping Up ↑ H. Naito include: In vivo antiproliferative effect of NS-187, a dual Bcr-Abl / Lyn tyrosine kinase inhibitor, on leukemic cells harbourage ring-Abl kinase domain mutations. In: . 6. 6. 6. Leukemia Research 30/2006, pp 1443–1446, PMID 16546254 . 7. Jumping Up ↑ ClinicalTrials.gov: Study of Bafetinib as Treatment for relapsed or Refractory Chronic Lymphocytic Leukemia B-Cell (B-CLL). Retrieved on June 17, 2011th 8. Jumping Up ↑ ClinicalTrials.gov: Study of Bafetinib (INNO-406) as Treatment for Patients With Hormone-Refractory Prostate Cancer (PROACT). Retrieved on June 17, 2011th 9. Jumping Up ↑ Food and Drug Administration: Database summary of 27 December 2006. Accessed on 16 September 2009.