Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777
Bibliographic record
Abstract
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".