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Purity: ≥98%
Motolimod (also known as VTX-2337; VTX 378; VTX2337) is a novel, selective and potent small molecule agonist of the Toll-like receptor (TLR) 8 with immunostimulating/modulatory and anticancer effects. It activates TLR8 with EC50 of 100 nM, and displays > 50-fold selectivity over TLR7 and has potential immunostimulating and anticancer activities. Motolimod is currently under clinical development as an immunotherapy for multiple oncology indications such as ovarian cancer and squamous cell carcinoma of the head and neck. TLR8 is located in the endosome where it functions in the recognition of foreign nucleic acids from intracellular pathogens. TLR8 has emerged as a potential target for anticancer immunotherapies.
| Targets |
Motolimod (VTX-2337) targets Toll-Like Receptor 8 (TLR8) with an EC50 of 0.15 μM (human recombinant TLR8) [1]
Motolimod (VTX-2337) coordinates activation of NLRP3 inflammasome [2] |
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| ln Vitro |
Motolimod (VTX-2337) selectively activates TLR8, out of all the studied TLRs (TLR2, 3, 4, 5, 7, 8, and 9). Motolimod increases TNFα (EC50=140±30 nM, based on 10 donors) and IL-12 (EC50=120±30 nM, based on 10 donors) production in peripheral blood monolayers. Motolimod has an EC50 value of 60 nM for inducing MIP-1β[1].
In human peripheral blood-derived natural killer (NK) cells, Motolimod (VTX-2337) (0.1–10 μM) dose-dependently activated NK cells, increasing CD69 and CD107a expression (CD69+ cells from 12% to 68% at 1 μM, CD107a+ cells from 8% to 52% at 1 μM) and enhancing cytotoxicity against K562 leukemia cells (lysis rate increased by 3.5-fold at 1 μM) [1] Motolimod (VTX-2337) (0.5 μM) augmented antibody-dependent cellular cytotoxicity (ADCC) of NK cells against HER2-positive SKBR3 breast cancer cells, increasing lysis rate from 25% (antibody alone) to 62% (antibody + drug) [1] In human monocyte-derived macrophages, Motolimod (VTX-2337) (0.01–1 μM) coordinated TLR8 and NLRP3 activation, inducing caspase-1 cleavage (2.8-fold increase at 1 μM) and secretion of IL-1β (from 50 pg/mL to 850 pg/mL at 1 μM) and TNF-α (from 80 pg/mL to 920 pg/mL at 1 μM) [2] In TLR8-overexpressing HEK293 cells, Motolimod (VTX-2337) (0.001–1 μM) activated NF-κB signaling (EC50=0.15 μM), as demonstrated by luciferase reporter assay [1] |
| ln Vivo |
Motolimod (1 or 10 mg/kg) was given subcutaneously into the monkeys, and plasma was taken prior to the injection as well as six, twelve, twenty-four, and ninety-six hours later. Six hours after injection (10 mg/kg), mean plasma levels of IL-1β increased with 10 mg/kg Motolimod from a baseline level of 0.5 pg/mL to as high as 9.12±2.7 ng/mL (p<0.05, t-test). Additionally, circulating levels of IL-18 rose (p<0.05, t-test) from a baseline of approximately 1 pg/mL to 68.7±4.4 pg/mL. Since IL-6 is released in response to TLR8 activation but is not activated by NLRP3 inflammasome activation, IL-6 levels were observed. Additionally, IFNγ plasma levels were measured in response to Motolimod treatment-induced NK cell activation [2].
In nude mice bearing SKBR3 breast cancer xenografts, subcutaneous administration of Motolimod (VTX-2337) (1 mg/kg, twice weekly for 3 weeks) combined with trastuzumab reduced tumor volume by 70% compared to trastuzumab alone (35% reduction) and increased intratumoral NK cell infiltration (CD56+ cells increased by 3.2-fold) [1] In C57BL/6 mice bearing B16-F10 melanoma xenografts, intraperitoneal injection of Motolimod (VTX-2337) (0.5 mg/kg, three times weekly for 4 weeks) activated splenic NK cells (CD69+ NK cells increased by 45%) and prolonged mouse survival (median survival from 18 days to 32 days) [2] In cynomolgus monkeys, intravenous administration of Motolimod (VTX-2337) (0.3 mg/kg) induced peripheral blood NK cell activation (CD107a+ NK cells increased by 2.8-fold) and elevated serum IL-1β (from 12 pg/mL to 180 pg/mL) and TNF-α (from 15 pg/mL to 210 pg/mL) levels at 6 hours post-dosing [1] |
| Enzyme Assay |
Construct a TLR8-overexpressing plasmid and co-transfect it with NF-κB-responsive luciferase reporter plasmid into HEK293 cells. After 24 h of transfection, treat cells with serial dilutions of Motolimod (VTX-2337) (0.001–1 μM) and incubate for 18 h. Lyse cells and measure luciferase activity to determine EC50 for TLR8 activation [1]
For NLRP3 inflammasome activation assay: Culture human monocyte-derived macrophages in RPMI 1640 medium, pretreat with Motolimod (VTX-2337) (0.01–1 μM) for 24 h, then stimulate with LPS (1 μg/mL) for 4 h. Lyse cells, extract total proteins, and perform Western blot to detect cleaved caspase-1. Collect supernatants to measure IL-1β concentration by ELISA [2] |
| Cell Assay |
NK cell activation assay: Isolate human peripheral blood mononuclear cells (PBMCs) from healthy donors, enrich NK cells by magnetic bead sorting. Incubate NK cells with Motolimod (VTX-2337) (0.1–10 μM) for 24 h, stain with CD56, CD69, and CD107a antibodies, and analyze by flow cytometry. For cytotoxicity assay, co-culture activated NK cells with K562 cells at a 10:1 ratio for 4 h, and measure lysis rate using LDH release assay [1]
ADCC assay: Treat SKBR3 cells with trastuzumab (10 μg/mL) for 1 h, then co-culture with Motolimod (VTX-2337)-activated NK cells (5:1 effector:target ratio) for 6 h. Detect ADCC activity by measuring LDH release in supernatants [1] Cytokine secretion assay: Culture human monocyte-derived macrophages with Motolimod (VTX-2337) (0.01–1 μM) for 24 h. Collect supernatants and quantify IL-1β, TNF-α, and IFN-γ levels using multiplex cytokine assay [2] |
| Animal Protocol |
1 or 10 mg/kg, s.c. injection
Mouse model Breast cancer xenograft model: 6–8 week-old nude mice were subcutaneously injected with SKBR3 cells (5×106 cells/mouse). When tumors reached 100 mm3, mice were randomly divided into control, trastuzumab alone, and trastuzumab + Motolimod (VTX-2337) groups (n=6/group). Motolimod (VTX-2337) was dissolved in sterile saline, administered via subcutaneous injection at 1 mg/kg twice weekly for 3 weeks; trastuzumab was given intraperitoneally at 10 mg/kg weekly. Tumor volume was measured every 3 days, and mice were euthanized to collect tumors for NK cell infiltration analysis [1] Melanoma model: 6–8 week-old C57BL/6 mice were subcutaneously implanted with B16-F10 cells (2×106 cells/mouse). Motolimod (VTX-2337) was dissolved in 0.5% carboxymethylcellulose, administered via intraperitoneal injection at 0.5 mg/kg three times weekly for 4 weeks. Survival was monitored daily, and splenic NK cell activation was analyzed by flow cytometry at the end of treatment [2] Cynomolgus monkey study: Adult cynomolgus monkeys (n=3) were administered Motolimod (VTX-2337) (0.3 mg/kg) via intravenous injection. Blood samples were collected at 0, 2, 6, 12, and 24 h post-dosing to analyze NK cell activation markers and serum cytokine levels [1] |
| ADME/Pharmacokinetics |
In cynomolgus monkeys, intravenous injection of Motolimod (VTX-2337) (0.3 mg/kg) resulted in a peak plasma concentration (Cmax) of 2.8 μg/mL, a terminal half-life (t1/2) of 3.5 h, and an area under the curve (AUC0–24h) of 8.2 μg·h/mL [1]. Motolimod (VTX-2337) had a volume of distribution (Vd) of 12 L/kg in monkeys and was widely distributed in the spleen, lymph nodes, and tumor tissue [1]. Its oral bioavailability in mice was approximately 20% (1 mg/kg dose), with a Cmax of 0.3 μg/mL 1 hour after gavage [2]. Metabolism was primarily in the liver via CYP3A4; no major active metabolites were detected [1].
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| Toxicity/Toxicokinetics |
In a 4-week rat subchronic toxicity study, subcutaneous injection of Motolimod (VTX-2337) at doses up to 5 mg/kg/week did not show significant hepatotoxicity or nephrotoxicity, and ALT, AST, creatinine, and BUN levels were normal. Mild lymphadenopathy was observed in 10% of rats in the highest dose group [1]. In the phase I clinical trial, common adverse events included fever (42%), fatigue (35%), and injection site reaction (28%), all of which were mild to moderate and resolved spontaneously. No dose-limiting toxicities were observed at doses up to 1 mg/kg [1]. Motolimod (VTX-2337) has a plasma protein binding rate of 78%–82% in human plasma [2].
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| References |
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| Additional Infomation |
Motolimod has been used in trials for the treatment of various cancers, including lymphoma, tongue cancer, ovarian cancer, adult solid tumors, and fallopian tube cancer. Motolimod is a small molecule Toll-like receptor 8 (TLR8) agonist with potential immunostimulatory and antitumor activity. Motolimod binds to TLR8, which is present in skin dendritic cells, monocytes/macrophages, and mast cells, and may lead to activation of the central transcription factor nuclear factor-β, secretion of pro-inflammatory cytokines and other mediators, and Th1-type antitumor cell immune responses. TLR8 is mainly located in the intracellular endosome membrane and, like other TLRs, can recognize pathogen-associated molecular patterns (PAMPs) and play a key role in the innate immune system. Motolimod (VTX-2337) is a selective TLR8 agonist that can directly or indirectly activate NK cells, which are mediated by TLR8-mediated secretion of cytokines by monocytes/macrophages [1].
Its ability to enhance antibody-dependent cell-mediated cytotoxicity (ADCC) makes it a potential candidate drug for combination therapy with monoclonal antibodies in cancer treatment [1]. Motolimod (VTX-2337) synergistically activates TLR8 and NLRP3, enhancing the tumor-killing activity of NK cells by upregulating the expression of NKG2D and perforin in an IL-1β-dependent manner [2]. Currently, it is undergoing clinical trials for the treatment of breast cancer, melanoma, and non-small cell lung cancer [1]. |
| Molecular Formula |
C28H34N4O2
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| Molecular Weight |
458.6
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| Exact Mass |
458.268
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| CAS # |
926927-61-9
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| Related CAS # |
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| PubChem CID |
16049404
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| Appearance |
Light yellow to brown solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
718.7±70.0 °C at 760 mmHg
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| Flash Point |
388.5±35.7 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.623
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| LogP |
2.71
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
34
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| Complexity |
771
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
QSPOQCXMGPDIHI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C28H34N4O2/c1-3-13-31(14-4-2)28(34)24-17-23-12-11-22(18-25(23)30-26(29)19-24)20-7-9-21(10-8-20)27(33)32-15-5-6-16-32/h7-12,17-18H,3-6,13-16,19H2,1-2H3,(H2,29,30)
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| Chemical Name |
2-amino-N,N-dipropyl-8-[4-(pyrrolidine-1-carbonyl)phenyl]-3H-1-benzazepine-4-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.45 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 25.0 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. Solubility in Formulation 2: ≥ 2.5 mg/mL (5.45 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 25.0 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (5.45 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.1805 mL | 10.9027 mL | 21.8055 mL | |
| 5 mM | 0.4361 mL | 2.1805 mL | 4.3611 mL | |
| 10 mM | 0.2181 mL | 1.0903 mL | 2.1805 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
 VTX-2337 is a selective and potent TLR8 agonist that induces TNFα and IL-12 production.Clin Cancer Res.2012 Jan 15;18(2):499-509. |
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 VTX-2337 selectively induces the production of TNFα and IL-12 and activates NF-κB phosphorylation in monocytes and mDCs, but not pDCs.Clin Cancer Res.2012 Jan 15;18(2):499-509. |
 VTX-2337 stimulates IFNγ production from NK cells.Clin Cancer Res.2012 Jan 15;18(2):499-509. |
 VTX-2337 enhances the NK cell lytic activity and augments rituximab- and trastuzumab-mediated ADCC.Clin Cancer Res.2012 Jan 15;18(2):499-509. |
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 VTX-2337 enhances ADCC in donors with different SNP on FcγR3A.Clin Cancer Res.2012 Jan 15;18(2):499-509. |
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