Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777.
GMX1778 was recently shown to function as a potent inhibitor of nicotinamide phosphoribosyl transferase. To translate the discovery of GMX1778 mechanism of action into optimal clinical use of its intravenously administered prodrug, GMX1777, the efficacy of GMX1777 was evaluated in xenograft models and the pharmacokinetic profile of GMX1778 and its effect on nicotinamide adenine dinucleotide cellular levels was measured by liquid chromatography/mass spectrometry. Consistent with the requirement for a prolonged exposure for cytotoxicity in vitro, a dose of 75 mg/kg of GMX1777 administered as two bolus intravenous injections in 1 day were not effective at reducing the growth of multiple myeloma (IM-9) tumors, whereas the same dose of GMX1777 administered over a 24 h intravenous infusion caused tumor regression in the IM-9 model, a small-cell lung cancer (SHP-77) model, and a colon carcinoma (HCT-116) model. A 72 h continuous intravenous infusion of GMX1777 was also effective in the IM-9 model, but was associated with a smaller therapeutic index. GMX1777 at a dose of 75 mg/kg administered over a 24 h intravenous infusion produced GMX1778 steady-state plasma levels of approximately 1 microg/ml and caused nicotinamide adenine dinucleotide levels to decrease significantly in tumors. Consistent with the GMX1778 mechanism of action, nicotinic acid protected mice treated with a lethal dose of GMX1777. These data support the design of an open-label, dose-escalation trial, in which patients with refractory solid tumors and lymphomas receive 24 h infusions of GMX1777 as a single agent in 3-week cycles. Furthermore, these results indicate that nicotinic acid is a potent antidote to treat GMX1777 overdose.
Beauparlant
Pierre
P
Gemin X Pharmaceuticals Inc., Montréal, Quebec, Canada. Pbeauparlant@geminx.com
Bédard
Dominique
D
Bernier
Cynthia
C
Chan
Helen
H
Gilbert
Karine
K
Goulet
Daniel
D
Gratton
Michel-Olivier
MO
Lavoie
Manon
M
Roulston
Anne
A
Turcotte
Emilie
E
Watson
Mark
M
D000230:Adenocarcinoma / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D018288:Carcinoma, Small Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor / Q000637:transplantation; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000473:pathology; D003486:Cyanides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D016207:Cytokines / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006146:Guanidines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy / Q000473:pathology; D009243:NAD / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D009525:Niacin / Q000378:metabolism; D009536:Niacinamide / Q000378:metabolism; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
C541789:1-(2-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)ethoxycarbonyloxymethyl)-4-(N'-cyano-N''-(6-(4-chlorophenoxy)hexyl)-N-guanidino)pyridinium; D000970:Antineoplastic Agents; D003486:Cyanides; D016207:Cytokines; D006146:Guanidines; C401312:N-(6-chlorophenoxyhexyl)-N''-cyano-N''-4-pyridylguanidine; D009363:Neoplasm Proteins; D011355:Prodrugs; D009243:NAD; D009536:Niacinamide; D009525:Niacin; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human