The goal of this clinical research study is to learn if obatoclax mesylate can help to control systemic mastocytosis. The safety of this drug will also be tested.

Start Date01 Jun 2009

Sponsor / Collaborator

The University of Texas MD Anderson Cancer Center

[+1]

EUCTR2008-001679-31-GB / Not yet recruitingPhase 1/2

A Phase I Followed by a Randomized, Phase II Study of Carboplatin and Etoposide with or without Obatoclax Administered Every 3 Weeks to Patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC)

Start Date20 Feb 2009

Sponsor / Collaborator

Gemin X Pharmaceuticals US, Inc.

NCT00724841 / TerminatedPhase 1/2

A Multi-Center, Open-Label, Phase I/II Study of GEM1777 in Combination With Temozolomide Administered Every 4 Weeks to Patients With Metastatic Melanoma

Obatoclax Mesylate (GMX1777) is a water-soluble, intravenously-administered pro-drug of GMX1778. GMX1777 is rapidly converted to GMX1778 in vivo. GMX1778 has potent anti-tumor activity against a variety of cell lines and models from different tumor origins.

Start Date01 Jun 2008

Sponsor / Collaborator

Gemin X Pharmaceuticals US, Inc.

100 Clinical Results associated with Gemin X Pharmaceuticals US, Inc.

0 Patents (Medical) associated with Gemin X Pharmaceuticals US, Inc.

Literatures (Medical) associated with Gemin X Pharmaceuticals US, Inc.

01 Jan 2011·Journal of VirologyQ2 · MEDICINE

Genetic Analysis of B55α/Cdc55 Protein Phosphatase 2A Subunits: Association with the Adenovirus E4orf4 Protein

Q2 · MEDICINE

Article

Author: Zhang, Zhiying ; Chan, Francine ; Li, Suiyang ; Roopchand, Diana E. ; Marcellus, Richard C. ; Mui, Melissa Z. ; Berghuis, Albert M. ; Branton, Philip E. ; Blanchette, Paola

ABSTRACT The human adenovirus E4orf4 protein is toxic in both human tumor cells and Saccharomyces cerevisiae . Previous studies indicated that most of this toxicity is dependent on an interaction of E4orf4 protein with the B55 class of regulatory subunits of protein phosphatase 2A (PP2A) and in yeast with the B55 homolog Cdc55. We have found previously that E4orf4 inhibits PP2A activity against at least some substrates. In an attempt to understand the mechanism of this inhibition, we used a genetic approach to identify residues in the seven-bladed β-propeller proteins B55α and Cdc55 required for E4orf4 binding. In both cases, amino-terminal polypeptides composed only of blade 1 and at least part of blade 2 were found to bind E4orf4 and overexpression blocked E4orf4 toxicity in yeast. Furthermore, certain amino acid substitutions in blades 1 and 2 within full-length B55α and Cdc55 resulted in loss of E4orf4 binding. Recent mutational analysis has suggested that segments of blades 1 and 2 present on the top face of B55α form part of the “substrate-binding groove.” Additionally, these segments are in close proximity to the catalytic C subunit of the PP2A holoenzyme. Thus, our results are consistent with the hypothesis that E4orf4 binding could affect the access of substrates, resulting in the failure to dephosphorylate some PP2A substrates.

01 Nov 2009·Molecular and Cellular BiologyQ3 · BIOLOGY

The Small Molecule GMX1778 Is a Potent Inhibitor of NAD⁺ Biosynthesis: Strategy for Enhanced Therapy in Nicotinic Acid Phosphoribosyltransferase 1-Deficient Tumors

Q3 · BIOLOGY

Article

Author: Bédard, Dominique ; Marcellus, Richard ; Nguyen, Mai ; Lavoie, Manon ; Beauparlant, Pierre ; Koch, Elizabeth ; Berger, Alvin ; Roulston, Anne ; Branchaud, Stéphane ; Turcotte, Émilie ; Khadir, Abdelkrim ; Chan, Helen ; Jang, Anne ; Dairi, Kenza ; Gilbert, Karine ; Mitchell, Matthew ; Gratton, Michel-Olivier ; Goulet, Daniel ; Billot, Xavier ; Watson, Mark ; Paquette, Denis ; Lawless, Michael ; Isakau, Henady ; Shore, Gordon C. ; Bernier, Cynthia ; Bélec, Laurent

ABSTRACT GMX1777 is a prodrug of the small molecule GMX1778, currently in phase I clinical trials for the treatment of cancer. We describe findings indicating that GMX1778 is a potent and specific inhibitor of the NAD + biosynthesis enzyme nicotinamide phosphoribosyltransferase (NAMPT). Cancer cells have a very high rate of NAD + turnover, which makes NAD + modulation an attractive target for anticancer therapy. Selective inhibition by GMX1778 of NAMPT blocks the production of NAD + and results in tumor cell death. Furthermore, GMX1778 is phosphoribosylated by NAMPT, which increases its cellular retention. The cytotoxicity of GMX1778 can be bypassed with exogenous nicotinic acid (NA), which permits NAD + repletion via NA phosphoribosyltransferase 1 (NAPRT1). The cytotoxicity of GMX1778 in cells with NAPRT1 deficiency, however, cannot be rescued by NA. Analyses of NAPRT1 mRNA and protein levels in cell lines and primary tumor tissue indicate that high frequencies of glioblastomas, neuroblastomas, and sarcomas are deficient in NAPRT1 and not susceptible to rescue with NA. As a result, the therapeutic index of GMX1777 can be widended in the treatment animals bearing NAPRT1-deficient tumors by coadministration with NA. This provides the rationale for a novel therapeutic approach for the use of GMX1777 in the treatment of human cancers.

01 Sep 2009·Journal of VirologyQ2 · MEDICINE

The Adenovirus E4orf4 Protein Induces G ₂ /M Arrest and Cell Death by Blocking Protein Phosphatase 2A Activity Regulated by the B55 Subunit

Q2 · MEDICINE

Article

Author: Miron, Marie-Joëlle ; Branton, Philip E. ; Zhang, Zhiying ; McQuoid, Monica J. ; Brignole, Claudine ; Binda, Olivier ; Li, Suiyang ; Thirlwell, Sara ; Ashby, Danita ; Marcellus, Richard ; Chan, Helen ; Pallas, David C.

ABSTRACT Human adenovirus E4orf4 protein is toxic in human tumor cells. Its interaction with the Bα subunit of protein phosphatase 2A (PP2A) is critical for cell killing; however, the effect of E4orf4 binding is not known. Bα is one of several mammalian B-type regulatory subunits that form PP2A holoenzymes with A and C subunits. Here we show that E4orf4 protein interacts uniquely with B55 family subunits and that cell killing increases with the level of E4orf4 expression. Evidence suggesting that Bα-specific PP2A activity, measured in vitro against phosphoprotein substrates, is reduced by E4orf4 binding was obtained, and two potential B55-specific PP2A substrates, 4E-BP1 and p70 S6K , were seen to be hypophosphorylated in vivo following expression of E4orf4. Furthermore, treatment of cells with low levels of the phosphatase inhibitor okadaic acid or coexpression of the PP2A inhibitor I 1PP2A enhanced E4orf4-induced cell killing and G 2 /M arrest significantly. These results suggested that E4orf4 toxicity results from the inhibition of B55-specific PP2A holoenzymes, an idea that was strengthened by an observed growth arrest resulting from treatment of H1299 cells with Bα-specific RNA interference. We believe that E4orf4 induces growth arrest resulting in cell death by reducing the global level of B55-specific PP2A activity, thus preventing the dephosphorylation of B55-specific PP2A substrates, including those involved in cell cycle progression.

100 Deals associated with Gemin X Pharmaceuticals US, Inc.

100 Translational Medicine associated with Gemin X Pharmaceuticals US, Inc.

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Current Projects

Drug(Targets)	Indications	Global Highest Phase

Temozolomide ( DNA )	Metastatic melanoma More	Discontinued
Teglarinad Chloride ( NAMPT )	Melanoma More	Discontinued
Obatoclax mesylate ( Bcl-2 )	Systemic Mastocytosis More	Discontinued
Rituximab ( CD20 )	Follicular Lymphoma More	Pending
Bortezomib ( Proteasome )	Mantle cell lymphoma refractory More	Pending

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