EB1627: a soluble prodrug of the potent anticancer cyanoguanidine CHS828

Binderup, Ernst; Björkling, Fredrik; Hjarnaa, Pernille V.; Latini, Scilla; Baltzer, Bodil; Carlsen, Morten; Binderup, Lise

doi:10.1016/j.bmcl.2005.03.064

Cited by 44 publications

(29 citation statements)

References 5 publications

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“…GMX1778 (formerly CHS-828) is a competitive inhibitor of NAMPT whose potency for NAMPT in vitro and cell growth inhibition is in the low nanomolar range (4). GMX1777 is a soluble prodrug of GMX used for in vivo studies (5,6). NAMPT inhibitors, including GMX1778 (GMX) and FK866, have shown preclinical activity alone and in combination with several therapeutic DNA-damaging agents, but the mechanism of synergy has not been clearly elucidated (7)(8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

Synergy between the NAMPT Inhibitor GMX1777(8) and Pemetrexed in Non–Small Cell Lung Cancer Cells Is Mediated by PARP Activation and Enhanced NAD Consumption

et al. 2014

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GMX1778 and its prodrug GMX1777 represent a new class of cancer drugs that targets nicotinamide phosphoribosyltransferase (NAMPT) as a new strategy to interfere with biosynthesis of the key enzymatic cofactor NAD, which is critical for a number of cell functions, including DNA repair. Using a genome-wide synthetic lethal siRNA screen, we identified the folate pathway-related genes, deoxyuridine triphosphatase and dihydrofolate reductase, the silencing of which sensitized non-small cell lung carcinoma (NSCLC) cells to the cytotoxic effects of GMX. Pemetrexed is an inhibitor of dihydrofolate reductase currently used to treat patients with nonsquamous NSCLC. We found that combining pemetrexed with GMX1777 produced a synergistic therapeutic benefit in A549 and H1299 NSCLC cells in vitro and in a mouse A549 xenograft model of lung cancer. Pemetrexed is known to activate PARPs, thereby accelerating NAD consumption. Genetic or pharmacologic blockade of PARP activity inhibited this effect, impairing cell death by pemetrexed either alone or in combination with GMX1777. Conversely, inhibiting the base excision repair pathway accentuated NAD decline in response to GMX and the cytotoxicity of both agents either alone or in combination. These findings provide a mechanistic rationale for combining GMX1777 with pemetrexed as an effective new therapeutic strategy to treat nonsquamous NSCLC. Cancer Res; 74(21); 5948-54. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Synergy between the NAMPT Inhibitor GMX1777(8) and Pemetrexed in Non–Small Cell Lung Cancer Cells Is Mediated by PARP Activation and Enhanced NAD Consumption

et al. 2014

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“…1,2 To overcome the variable absorption of CHS 828 in man 3 the soluble prodrug EB 1627 4,5 (2a) has been prepared. For biological studies 6 tritiated CHS 828 (1d) as well as its tritiated prodrug EB 1627 (2d) were needed.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of tritium labelled CHS 828 and its prodrug EB 1627

Schou¹,

Hunneche²,

Binderup³

et al. 2005

J Label Compd Radiopharm

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SummaryThe potent antitumoral cyanoguanidine CHS 828 and its prodrug EB 1627 have successfully been labelled with tritium. The pyridyl-3,5-dibromo derivative of CHS 828 was debrominated with tritium-gas using Pd/C catalyst to give [pyridyl-3,5-3 H 2 ]-CHS 828 with a radiochemical purity of 99.3% and a specific activity of 1960 GBq/ mmol. Similarly, the pyridyl-3-bromo derivative of the prodrug EB 1627 was debrominated with tritium-gas to give [pyridyl-3-3 H]-EB 1627 with a radiochemical purity of 98.1% and a specific activity of 894 GBq/mmol.

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“…Toxicity was dominated by gastrointestinal symptoms and thrombocytopenia [25]. To improve pharmacokinetics and water solubility, derivative EP1627 (also named GMX1777) was proposed as an alternative to CHS-828 [26]. Similarly, the d-ribofuranosyl derivative of FK866, called IS001, was prepared to improve poor water solubility of FK866.…”

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confidence: 99%