Colon cancer (HCT-116), small cell lung cancer (SHP-77) and IM-9 models can all show tumor regression in response to GMX1777 (75 mg/kg; intravenous infusion administered every 24 hours) [2]. In vivo, GMX1777 (50–100 mg/kg/d, intramuscular injection for 5 days) is efficacious against FaDu and C666-1 tumors when used in conjunction with or instead of local tumor irradiation [1]. In mouse plasma, GMX1777 (25–400 mg/kg; 24-hour intravenous infusion) quickly transforms into GMX1778, with GMX1777 having a half-life of less than 0.7 hours [2].

Animal/Disease Models: CB17 SCID/SCID female mice bearing subcutaneousIM-9 multiple myeloma tumors [2]
Doses: 18.75, 35, 75 mg/kg
Route of Administration: 24-hour intravenous (iv) (iv)infusion
Experimental Results: Induced almost complete tumor regression , and Dramatically improved tumor growth delay at the dose of 75mg/kg. 37.5 mg/kg moderately reduces IM-9 tumor growth.

Metabolism / Metabolites
GMX1777 is rapidly converted to GMX1778 in vivo through hydrolytic cleavage of an ester carbonate bond.

[1]. Efficacy of combining GMX1777 with radiation therapy for human head and neck carcinoma. Clin Cancer Res. 2010 Feb 1;16(3):898-911.

[2]. Preclinical development of the nicotinamide phosphoribosyl transferase inhibitor prodrug GMX1777. Anticancer Drugs. 2009 Jun;20(5):346-54.

GMX1777 is a water-soluble prodrug of the cyanoguanidine compound GMX1778 with potential antineoplastic activity. In vivo, apoptosis inducer GMX1777 is rapidly converted into GMX1778 through hydrolytic cleavage of a carbonate ester bond. Although the exact mechanism of action has yet to be fully elucidated, GMX1778 appears to antagonize nuclear factor-kappa B (NF-kB) transcription, resulting in the induction of tumor cell apoptosis.
Teglarinad Chloride is a water-soluble prodrug of a cyanoguanidine compound with potential antineoplastic activity. In vivo, teglarinad chloride is rapidly converted into active drug through hydrolytic cleavage of a carbonate ester bond. Although the exact mechanism of action has yet to be fully elucidated, the active drug appears to antagonize nuclear factor-kappa B (NF-kB) transcription, resulting in the induction of tumor cell apoptosis.

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Drug Indication
Intended for the treatment of solid tumors and lymphomas.

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Mechanism of Action
The cytotoxicity of GMX1777, a prodrug of GMX1778, occurs exclusively through its ability to selectively inhibit nicotinamide phosphoribosyl transferase (NAMPRT). Tumor cells have elevated NAMPRT, an enzyme involved in the biosynthesis of oxidized nicotinamide adenine dinucleotide (NAD+). These cells have a high rate of NAD+ turnover due to elevated glycolysis and high ADP-ribosylation activity required for DNA repair, genome stability and telomere maintenance. These latter characteristics make cancer cells more susceptible to NAMPRT inhibition than normal cells. Although the mechanism of action of GMX1778 was initially believed to include NF-κB inhibition, a transcriptional factor that plays a role in cancer cell survival, NF-κB inhibition occurs as a consequence of ATP loss following NAMPRT inhibition and NAD+ decline.

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Pharmacodynamics
GMX1777 exhibits unusually potent anti-tumor activity in preclinical animal models. The novel mechanism of action of GMX1778 supports the clinical use of GMX1777 as an anti-cancer agent. Moreover, the strong dependency of cancer cells on NAD+ to support DNA repair suggests a strong rationale for the use of GMX1777 in combination with DNA damaging agents for future trials.

C30H43N5O8CL+.CL-

672.59712

671.249

432037-57-5

766501-75-1 (cation);432037-57-5 (chloride);

9961434

White to off-white solid powder

158-159ºC

5.108

2

11

27

45

802

0

DAHMXVAETAAQOZ-UHFFFAOYSA-N

InChI=1S/C30H42ClN5O8.ClH/c1-38-16-17-39-18-19-40-20-21-41-22-23-43-30(37)44-25-36-13-10-27(11-14-36)35-29(34-24-32)33-12-4-2-3-5-15-42-28-8-6-26(31)7-9-28;/h6-11,13-14H,2-5,12,15-23,25H2,1H3,(H,33,34);1H

[4-[[N'-[6-(4-chlorophenoxy)hexyl]-N-cyanocarbamimidoyl]amino]pyridin-1-ium-1-yl]methyl 2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl carbonate;chloride

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~66.67 mg/mL (~99.12 mM)

Solubility in Formulation 1: ≥ 5 mg/mL (7.43 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 5 mg/mL (7.43 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 5 mg/mL (7.43 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 50.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)