Nicotinamide phosphoribosyltransferase (NAMPT).

Teglarinad chloride (GMX1777) is a water-soluble prodrug that is rapidly converted in vivo into the active compound GMX1778 (CHS-828), a potent and specific inhibitor of NAMPT with an IC50 of <20 nM. By inhibiting NAMPT, teglarinad chloride depletes cellular NAD+ levels, leading to energy depletion, oxidative stress, and cell death in cancer cells. The compound is widely used in oncology and metabolic research to explore cancer cell vulnerabilities, stress responses, and NAD+-dependent signaling.

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].

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In vivo, teglarinad chloride is a prodrug that is rapidly converted to the active compound GMX1778. GMX1778 is a potent NAMPT inhibitor with antitumor activity. The compound has been investigated for the treatment of various cancers, including lymphoma, leukemia, and solid tumors. Specific dosing regimens and detailed efficacy data are available from preclinical and clinical studies. Teglarinad chloride supports preclinical studies aimed at developing targeted treatments that exploit metabolic weaknesses in tumor cells.

NAMPT inhibition is assessed using in vitro biochemical assays with recombinant NAMPT enzyme and substrates (nicotinamide and ATP). The production of nicotinamide mononucleotide (NMN) is measured. IC50 values are calculated from dose-response curves. Cellular activity is assessed by measuring NAD+ levels in cells treated with teglarinad chloride or its active metabolite GMX1778.

Cellular activity is evaluated in cancer cell lines. Cells are treated with teglarinad chloride or GMX1778 at various concentrations (typically 0.001-100 µM) for 24-72 hours. NAD+ levels are measured by enzymatic cycling assays or LC-MS. Cell proliferation is measured by MTT, MTS, or CellTiter-Glo assays. ATP levels are measured by luciferase-based assays. Apoptosis is measured by caspase-3/7 activation or Annexin V staining. Oxidative stress is measured by assessing ROS levels.

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.

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In vivo efficacy is studied in mouse xenograft models of cancer, including lymphoma, leukemia, and solid tumors. Teglarinad chloride is administered via various routes (oral, intravenous) at doses determined from pharmacokinetic and tolerability studies. Tumor growth is measured by caliper twice weekly, and tumor volume is calculated. NAD+ levels are measured in tumor tissue. Pharmacodynamic markers including NAD+ depletion, ATP depletion, and apoptosis are assessed in tumor tissue.

Metabolism/Metabolite
GMX1777 is rapidly converted to GMX1778 in vivo via the hydrolytic cleavage of ester carbonate bonds.

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Teglarinad chloride has a molecular formula of C30H43Cl2N5O8 and a molecular weight of 672.60 g/mol. CAS Number: 432037-57-5. Purity: ≥98%. The compound is a water-soluble prodrug. It is soluble in water and DMSO. Storage: store at -20°C for long-term stability, protected from light and moisture. Detailed pharmacokinetic parameters including half-life, oral bioavailability, and plasma protein binding are available from preclinical and clinical studies.

Safety data for teglarinad chloride are available from preclinical and clinical studies. As a NAMPT inhibitor that depletes NAD+ levels, it may cause metabolic stress and toxicity in normal cells, particularly in tissues with high NAD+ turnover. Common adverse events may include gastrointestinal toxicity, myelosuppression, and fatigue. The compound is for research use only and not for human therapeutic applications without appropriate regulatory approval. Standard laboratory safety practices should be followed during handling, including the use of personal protective equipment and adequate ventilation.

[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, possessing potential antitumor activity. In vivo, the apoptosis inducer GMX1777 is rapidly converted to GMX1778 via the hydrolytic cleavage of its carbonate bonds. Although its exact mechanism of action is not fully elucidated, GMX1778 appears to antagonize the transcription of nuclear factor-κB (NF-κB), thereby inducing tumor cell apoptosis. Tegiraline chloride is a water-soluble prodrug of the cyanoguanidine compound, possessing potential antitumor activity. In vivo, tegiraline chloride is rapidly converted to the active drug via the hydrolytic cleavage of its carbonate bonds. Although its exact mechanism of action is not fully elucidated, the active drug appears to antagonize the transcription of nuclear factor-κB (NF-κB), thereby inducing tumor cell apoptosis. Drug Indications: For the treatment of solid tumors and lymphomas. Mechanism of Action The cytotoxicity of GMX1777 (a prodrug of GMX1778) is achieved entirely through its selective inhibition of nicotinamide phosphoribosyltransferase (NAMPRT). Tumor cells exhibit elevated NAMPRT levels; NAMPRT is an enzyme involved in the biosynthesis of oxidized nicotinamide adenine dinucleotide (NAD+). These cells have a high NAD+ turnover rate due to enhanced glycolysis and high ADP-ribosylation activity required for DNA repair, genome stability, and telomere maintenance. This latter characteristic makes cancer cells more susceptible to NAMPRT inhibition than normal cells. Although the mechanism of action of GMX1778 was initially thought to include inhibition of NF-κB (a transcription factor that plays a role in cancer cell survival), NF-κB inhibition is actually due to ATP loss resulting from NAMPRT inhibition and decreased NAD+ levels. Pharmacodynamics GMX1778 exhibited exceptionally potent antitumor activity in preclinical animal models. The novel mechanism of action of GMX1778 supports its clinical application as an anticancer drug. Furthermore, the high dependence of cancer cells on NAD+ (which supports DNA repair) suggests that there is a strong theoretical basis for the combined use of GMX1778 with DNA-damaging agents in future trials.

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Teglarinad chloride (GMX1777) is a research tool compound and clinical candidate for studying NAMPT biology and cancer metabolism. It is not approved for clinical use. The compound is a water-soluble prodrug of the potent NAMPT inhibitor GMX1778 (CHS-828). By targeting NAD+ biosynthesis, teglarinad chloride exploits the metabolic vulnerability of cancer cells that are highly dependent on NAD+ for proliferation and survival. It is used in oncology research to study the role of NAD+ metabolism in cancer and to develop targeted therapies that disrupt cancer cell metabolism. Teglarinad chloride is also used in metabolic research to study NAD+-dependent signaling pathways and stress responses.

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.)