TLN-4601, a novel anticancer agent, inhibits Ras signaling post Ras prenylation and before MEK activation

Boufaied, Nadia; Wioland, My-Anh; Falardeau, Pierre; Gourdeau, Henriette

doi:10.1097/cad.0b013e328337f373

Cited by 21 publications

(20 citation statements)

References 42 publications

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“…Potent therapeutic effects of BU-4664L (diazepinomicin) in human breast cancer MDA-MB-231 and prostate cancer PC-3 xenograft mouse experiments have been reported [25]. Additionally, BU-4664L was indicated to inhibit the Ras-MAPK (mitogen activate protein kinase) signaling pathway [26] which is responsible for cell growth, differentiation and survival. Ras is the most common oncogene in human cancer and Ras mutation is frequently associated with tumorigenesis.…”

Section: Bu-4664l a Cell Migration Inhibitor From Micromonospora Spmentioning

confidence: 93%

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Igarashi

2014

Handbook of Anticancer Drugs From Marine Origin

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Actinomycetes are the richest source of bioactive small molecules with high structural complexity and diversity which have been an inspiration to drug development. After the intensive screening efforts from soil-derived actinomycetes over a half century, it became necessary to exploit new microbial resources for discovering new drug leads. The deep-sea water in Toyama Bay is known as the 'specific deep-sea water of Japan Sea' because Sea of Japan is almost enclosed from the Pacific Ocean and the water exchanges very slowly with the neighboring seas. Furthermore, high dissolved oxygen concentration in this sea water gives rise to high biological productivity. As a part of investigation on the deep-sea water in Toyama Bay, we undertook the isolation of actinomycetes from deep-sea water for evaluation of bioactive compound production. This chapter summarizes the chemistry and biology of antitumor compounds produced by actinomycetes collected from the deep-sea water in Toyama Bay.Keywords Actinomycetes · Micromonospora · Deep-sea water · Antitumor compounds IntroductionToyama Bay is located in the northern shores of Honshu, Japan, and faced to Sea of Japan. The sea water present deeper than 300 m is called 'deep-sea water', which occupies about 60 % of the total volume of Toyama Bay. The deep-sea water of Toyama Bay has a low temperature, annually stable around 2 °C. The salinity is also stable at 34.0-34.1 g/kg, higher than that of surface sea water (32-33 g/kg). Utilization of the deep-sea water is being studied for commercial/industrial purposes such as aquatic culture of cold-water shrimps. As a part of investigation on the deep-sea water in Toyama Bay, we undertook the isolation of actinomycetes from

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Section: Bu-4664l a Cell Migration Inhibitor From Micromonospora Spmentioning

confidence: 93%

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Igarashi

2014

Handbook of Anticancer Drugs From Marine Origin

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“…Unfortunately, TL-4601 failed to significantly affect tumor progression at the doses given in patients and only transiently suppressed Ras-ERK MAPK signaling compared to the more marked reductions seen in laboratory studies (Campbell et al 2010, Boufaied et al 2010). Crizotinib (PF-02341066) is an orally available ATP-competitive selective inhibitor of ALK and MET tyrosine kinases that inhibits tyrosine phosphorylation on these receptors at nanomolar concentrations (McDermott et al 2008, Christensen et al 2007).…”

Section: Alk and Met In Relation To Current Therapiesmentioning

confidence: 85%

“…For most RTKs, including ALK and MET, there are three points of intracellular signal diversion which may mediate the transition from a normal cell to cancer cell (Figure 1). STAT (signal transducer and activation of transcription; STAT3, in particular), AKT (also known as protein kinase B), and Ras (‘rat sarcoma’; named from the first identified gene transcript in rat sarcomas) downstream signaling appear to be at once independently and interactively responsible for the oncogenic activities of both ALK and MET (Boufaied et al 2010, Zhang et al 2002, Chiarle et al 2005, Porter & Vaillancourt 1998, De Luca et al 2012). Though these three downstream components are highly dependent upon transduction factors such as Grb2, Gab1 and JAK, which respond more directly to RTK tyrosine phosphorylation, they represent intracellular turning points that individually promote oncogenic transition and tumor growth (Birchmeier et al 2003).…”

Section: Alk and Met In Glioblastomamentioning

confidence: 99%

Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma

et al. 2013

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Glioblastoma is the most common aggressive, highly glycolytic, and lethal brain tumor. In fact, it is among the most commonly diagnosed lethal malignancies, with thousands of new cases reported in the United States each year. Glioblastoma's lethality is derived from a number of factors including highly active pro-mitotic and pro-metastatic pathways. Two factors increasingly associated with the intracellular signaling and transcriptional machinery required for such changes are anaplastic lymphoma kinase (ALK) and the hepatocyte growth factor receptor (HGFR or, more commonly MET). Both receptors are members of the receptor tyrosine kinase (RTK) family, which has itself gained much attention for its role in modulating mitosis, migration, and survival in cancer cells. ALK was first described as a vital oncogene in lymphoma studies, but it has since been connected to many carcinomas, including non-small cell lung cancer and glioblastoma. As the receptor for HGF, MET has also been highly characterized and regulates numerous developmental and wound healing events which, when upregulated in cancer, can promote tumor progression. The wealth of information gathered over the last 30 years regarding these RTKs suggests three downstream cascades that depend upon activation of STAT3, Ras, and AKT. This review outlines the significance of ALK and MET as they relate to glioblastoma, explores the significance of STAT3, Ras, and AKT downstream of ALK/MET, and touches on the potential for new chemotherapeutics targeting ALK and MET to improve glioblastoma patient prognosis.

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“…TLN-4601 (formerly ECO-4601) is a structurally novel farnesylated dibenzodiazepinone that has potent inhibitory effects on the Ras-MAPK signaling pathway [3], the likely mechanism responsible for its demonstrated antitumor efficacy in a variety of tumor models including rat glioma xenografts [4]. TLN-4601 inhibits the Ras-MAPK signaling cascade by inhibiting the phosphorylation of downstream effector proteins, such as Raf and ERK, as well as depleting total Raf-1 protein levels [3,5].…”

Section: Introductionmentioning

confidence: 99%

“…TLN-4601 inhibits the Ras-MAPK signaling cascade by inhibiting the phosphorylation of downstream effector proteins, such as Raf and ERK, as well as depleting total Raf-1 protein levels [3,5]. TLN-4601 is also known to bind selectively to the peripheral benzodiazepine receptor (PBR), a receptor highly expressed on the surface of glioma tumours, and may be the reason leading to the observed accumulation of drug in xenograft gliomas at concentrations in the range of 200 times what is observed in normal tissues [6].…”

Section: Introductionmentioning

confidence: 99%

A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression

et al. 2011

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This phase II trial was undertaken to evaluate the efficacy of TLN-4601 in patients with glioblastoma (GBM) at first progression. TLN-4601 inhibits the Ras-MAPK signaling pathway, and in animal models crosses the blood-brain barrier and accumulates in implanted gliomas, possibly by binding specifically to the peripheral benzodiazepine receptor. A maximum of 40 patients with recurrent GBM were to be enrolled in this study. TLN-4601 was administered at a dose of 480 mg/m(2)/day by continuous intravenous (CIV) administration. Each 21-day cycle consisted of a 14-day CIV administration and a 7-day recovery period. Samples were obtained from all patients for pharmacokinetic evaluations (PK) and for Raf-1 and pERK biomarker assessment using immunohistochemistry and flow cytometry. Following enrollment of 20 patients, this study was terminated due to a lack of efficacy. Of 17 evaluable patients, 14 had MR scans performed after two cycles of TLN-4601. Of these 14 patients, three had stable disease and 11 had disease progression. Only three patients had MR scans performed after four cycles and all had evidence of radiographic progression. Serum PKs confirmed that patients were exposed to TLN-4601 at targeted drug levels. TLN-4601 was generally well tolerated although two patients discontinued treatment due to adverse events. Biomarker analysis did not show consistent changes. TLN-4601 infused via CIV at 480 mg/m(2)/day for 14 of 21 days is well tolerated by patients with progressive GBM. However, this agent is ineffective in progressive GBM when administered as monotherapy in this schedule.

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TLN-4601, a novel anticancer agent, inhibits Ras signaling post Ras prenylation and before MEK activation

Cited by 21 publications

References 42 publications

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Antitumor Compounds from Actinomycetes in Deep-sea Water of Toyama Bay

Targeting oncogenic ALK and MET: a promising therapeutic strategy for glioblastoma

A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression

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