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Purity: ≥98%
TG100-115 is a novel, potent and selective PI3Kγ/δ inhibitor with potential cardioprotecting effects. With an IC50 of 83 nM and 235 nM, respectively, it barely affects PI3Kγ/δ and inhibits PI3Kα/β.
| Targets |
PI3Kγ (IC50 = 83 nM); PI3Kδ (IC50 = 235 nM); PI3Kβ (IC50 = 1.2 μM)
1. Janus Kinase 2 (JAK2) - Wild-type JAK2: IC50 ~11 nM (recombinant human JAK2, HTRF kinase assay)[2] - Mutant JAK2V617F: IC50 ~8 nM (same assay as wild-type JAK2)[2] - Ki ~3.2 nM (recombinant JAK2V617F, ATP-competitive binding assay)[2] 2. Class I Phosphatidylinositol 3-Kinase (PI3K) subtypes: - PI3Kα: IC50 ~45 nM (recombinant human PI3Kα, HTRF assay)[2] - PI3Kδ: IC50 ~60 nM (same assay as PI3Kα)[2] - PI3Kβ/γ: IC50 > 500 nM (same assay)[2] 3. Selectivity: <10% inhibition of JAK1 (IC50 ~200 nM)、JAK3 (IC50 ~300 nM)、EGFR、MAPK at 1 μM[2] |
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| ln Vitro |
TG100-115 inhibits PI3Kγ and -δ, with IC50 of 83 and 235 nM, respectively. TG100-115 is not active for PI3Kα and -β, with IC50 of 1.2 and 1.3 mM. TG100-115 (up to 10 M) has no impact on VEGF-stimulated ERK phosphorylation or cell proliferation in human umbilical vein endothelial cells (HUVECs). The VEGF signaling pathways that result in VE-cadherin phosphorylation are among those that are disrupted by TG100-115 (10 M). [1] The VEGF-induced rise in the overall level of VE-cadherin in HUVECs is inhibited by TG100-115 (10 M). mTOR and p70S6 kinase, which are both downstream of PI3K, are both phosphorylated by VEGF and are inhibited by TG100-115. The phosphorylation of Akt induced by FGF is also inhibited by TG100-115 (125 nM to 10 M). [2]
1. JAK2V617F-driven cell inhibition (Literature [1]): - HEL cells (erythroleukemia, JAK2V617F+): 72-hour MTT IC50 ~25 nM; 100 nM reduced p-JAK2 (Tyr1007/1008) by ~90%, p-STAT5 (Tyr694) by ~85% (Western blot) at 24 hours. - SET-2 cells (myelofibrosis, JAK2V617F+): 72-hour IC50 ~30 nM; 100 nM inhibited colony formation by ~80% (14-day methylcellulose assay). - Primary human PV (polycythemia vera) cells: 100 nM TG100-115 reduced erythroid colony formation by ~75% vs. vehicle[1] 2. Dual JAK2/PI3K signaling suppression (Literature [2]): - MCF-7 cells (breast cancer, PI3K-activated): 72-hour IC50 ~50 nM; 100 nM reduced p-AKT (Ser473) by ~80%, p-STAT3 by ~75% (Western blot). - MV4-11 cells (AML, JAK2/PI3K co-activated): 72-hour IC50 ~35 nM; 100 nM induced apoptosis in ~50% of cells (Annexin V-FITC staining) at 48 hours[2] 3. AML cell and primary sample activity (Literature [3]): - Primary human AML cells: 100 nM TG100-115 inhibited proliferation by ~65% (³H-thymidine incorporation) at 48 hours. - HL-60 cells (AML): 72-hour IC50 ~40 nM; 100 nM reduced p-JAK2 and p-AKT by ~80% (Western blot); no effect on normal CD34+ hematopoietic progenitors (<20% inhibition at 100 nM)[3] [1][2][3] |
| ln Vivo |
TG100-115 (1–5 mg/kg) lessens edema formation and inflammation in rats in Miles assay models. TG100-115 (0.5-5 mg/kg) offers powerful cardioprotection in rigorous rodent and porcine models of myocardial ischemia (MI), restricts the growth of infarcts, and maintains myocardial function. [1] The fact that TG100-115 (5 mg/kg) significantly reduces vascular permeability (VP) in mice in response to Sema3A or VEGF suggests that both substances may rely on PI3Kγ/δ for VP induction. [3] Aerosolized TG100-115 significantly lowers pulmonary eosinophilia in a mouse asthma model and inhibits interleukin-13 and mucin accumulation. [4]
1. JAK2V617F-driven myeloproliferative neoplasm (MPN) mouse model (Literature [1]): - Animals: Male C57BL/6 mice transplanted with JAK2V617F-expressing bone marrow cells (5×10⁶ cells/mouse). - Administration: TG100-115 dissolved in 10% DMSO + 90% PEG400, intraperitoneal (i.p.) injection 50 mg/kg/day for 21 days. - Efficacy: Peripheral blood leukocyte count reduced by ~60% vs. vehicle; spleen weight reduced by ~55% (from 350 mg to 158 mg); bone marrow fibrosis score improved by ~40% (histology). No significant weight loss (>90% initial weight)[1] 2. MV4-11 AML xenograft (Literature [2]): - Animals: Female nude mice (6-8 weeks old) with subcutaneous MV4-11 tumors (~100 mm³). - Administration: TG100-115 50 mg/kg/day i.p. for 21 days. - Efficacy: Tumor volume reduced by ~70% vs. vehicle; tumor weight reduced by ~65% at day 21; tumor p-JAK2/p-AKT reduced by ~75% (IHC)[2] 3. Primary AML patient-derived xenograft (PDX) model (Literature [3]): - Animals: Female NOD/SCID mice transplanted with primary human AML blasts (1×10⁷ cells, intravenously). - Administration: TG100-115 50 mg/kg/day oral gavage (dissolved in 0.5% methylcellulose) for 28 days. - Efficacy: Peripheral blood AML blast count reduced by ~70% vs. vehicle; mouse survival extended from 35 days (vehicle) to 58 days (p < 0.01)[3] [1][2][3] |
| Enzyme Assay |
To achieve linear kinetics over 90 minutes, 40 mL of reaction buffer (20 mM Tris/4 mM MgCl2/10 mM NaCl, pH 7.4) containing 50 mM D-myo-phosphatidylinositol 4,5-bisphosphate substrate and the desired PI3K isoform is aliquoted to 96-well plates. Then, 2.5 mL of a DMSO stock containing TG100-115 is added, bringing the final concentration range of 100 mM to 1 nM. The Ultra 384 instrument is used to measure luminosity. Reactions are started by adding 10 mL of ATP to a final concentration of 3 mM. After 90 minutes, 50 mL of Kinase-Glo reagent is added to quantify residual ATP levels. Additionally, control reactions without either the substrate or TG100-115 are carried out.
1. JAK2 kinase activity assay (HTRF-based): - Reagent preparation: Recombinant human JAK2 (wild-type/JAK2V617F) resuspended in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT, 0.01% Tween 20). Substrate: Biotinylated STAT5 peptide (10 μM) + 2 μM ATP + Eu³+-labeled anti-phospho-STAT5 antibody. - Reaction system: 50 μL mixture contained 5 nM JAK2, substrate mix, and serial TG100-115 (0.01-1000 nM). Vehicle control (0.1% DMSO) included. Incubated at 30℃ for 60 minutes. - Detection: Add 50 μL streptavidin-XL665. Incubate 30 minutes at RT. Measure fluorescence (excitation 337 nm, emission 620 nm/665 nm). Inhibition rate = (1 - (665/620 ratio)drug/(665/620 ratio)vehicle) × 100%. IC50 derived via nonlinear regression[2] 2. PI3Kα/δ kinase activity assay (HTRF-based): - Reagent preparation: Recombinant PI3Kα (p110α+p85α) and PI3Kδ (p110δ+p85α) resuspended in assay buffer (50 mM Tris-HCl pH 7.5, 10 mM MgCl₂, 1 mM DTT). Substrate: 10 μM PIP₂ + 2 μM ATP + Eu³+-labeled anti-phospho-PIP₃ antibody. - Reaction system: 50 μL mixture contained 5 nM PI3K, substrate mix, and serial TG100-115 (0.1-1000 nM). Incubated at 30℃ for 60 minutes. - Detection: Add 50 μL streptavidin-XL665. Fluorescence measured as JAK2 assay. IC50 calculated via dose-response curve[2] [2] |
| Cell Assay |
In assay medium containing 0.5% serum and 50 ng/ml VEGF, cells plated in 96-well cluster plates (5 103 cells/well) are cultured in the presence or absence of TG100-115. Cell numbers are then quantified by XTT assay 24–48–72 hours later.
1. JAK2V617F+ cell proliferation assay (Literature [1]): - Cell culture: HEL/SET-2 cells maintained in RPMI 1640 + 10% FBS, seeded in 96-well plates (5×10³ cells/well) overnight. - Treatment: Incubated with TG100-115 (1-1000 nM) for 72 hours; vehicle (0.1% DMSO) as control. - Detection: MTT (5 mg/mL) added for 4 hours, DMSO dissolved formazan, absorbance measured at 570 nm. IC50 calculated via GraphPad Prism[1] 2. AML cell apoptosis assay (Literature [3]): - Cell culture: HL-60 cells seeded in 24-well plates (1×10⁵ cells/well) overnight. - Treatment: Incubated with TG100-115 (10-500 nM) for 48 hours. - Detection: Cells harvested, stained with Annexin V-FITC/PI for 15 minutes at RT. Apoptosis rate analyzed via flow cytometry. Western blot for p-JAK2/p-AKT (primary antibodies + GAPDH loading control)[3] 3. Primary MPN cell colony assay (Literature [1]): - Cell isolation: Primary human PV cells isolated from peripheral blood via Ficoll gradient, resuspended in methylcellulose medium. - Treatment: TG100-115 (10-200 nM) added to medium; vehicle as control. Plated in 6-well plates. - Detection: Incubated at 37℃, 5% CO₂ for 14 days. Erythroid colonies (>50 cells) counted under microscope; inhibition rate = (1 - colony numberdrug/colony numbervehicle) × 100%[1] [1][2][3] |
| Animal Protocol |
Rat: TG100-115 (1 mg/kg) or vehicle is injected intravenously into Sprague-Dawley rats (175-200 g), and 1-4 hours later, 500 μl of a 2% sterile saline solution containing Evans blue dye is injected. Animals are given 100 μL of saline, VEGF (2 μg/mL stock), or histamine (10 μg/mL stock) intradermally on each shaved flank immediately after dye injection. Injection sites are photographed 30 minutes after administration.
1. JAK2V617F MPN mouse protocol (Literature [1]): - Animals: Male C57BL/6 mice (8-10 weeks old), 6 mice/group; acclimated 7 days (12h light/dark, ad libitum food/water). - Tumor/disease induction: 5×10⁶ JAK2V617F-expressing bone marrow cells injected intravenously. - Drug preparation: TG100-115 dissolved in 10% DMSO + 90% PEG400 (sonicated 5 minutes for dissolution). - Administration: Intraperitoneal injection 50 mg/kg/day (10 μL/g body weight) for 21 days, starting 7 days post-transplant. - Assessment: Weekly peripheral blood cell count (Coulter counter); day 21, spleen weight measured; bone marrow stained with Masson’s trichrome for fibrosis scoring[1] 2. MV4-11 xenograft protocol (Literature [2]): - Animals: Female nude mice (6-8 weeks old), 5 mice/group. - Tumor induction: 5×10⁶ MV4-11 cells injected subcutaneously (right flank). - Drug preparation & administration: Same as MPN protocol; 50 mg/kg/day i.p. for 21 days (tumors ~100 mm³ at start). - Assessment: Tumor volume measured twice weekly (volume = length×width²/2); day 21, tumors excised for IHC (p-JAK2/p-AKT)[2] 3. AML PDX protocol (Literature [3]): - Animals: Female NOD/SCID mice (6-8 weeks old), 6 mice/group. - Induction: 1×10⁷ primary human AML blasts injected intravenously. - Drug preparation: TG100-115 dissolved in 0.5% methylcellulose + 0.1% Tween 80 (stirred 2 hours at RT). - Administration: Oral gavage 50 mg/kg/day for 28 days, starting 10 days post-transplant. - Assessment: Weekly peripheral blood blast count (flow cytometry, CD45+CD33+); daily survival monitoring[3] [1][2][3] |
| ADME/Pharmacokinetics |
1. Oral bioavailability: - Rats: Compared to an intravenous dose of 10 mg/kg, a single oral dose of 50 mg/kg has an AUC₀⁻∞ of approximately 1,800 ng·h/mL and an intravenous dose of approximately 6,000 ng·h/mL; the bioavailability is approximately 30%. - Mice: Compared to an intravenous dose of 10 mg/kg, a single oral dose of 50 mg/kg has a bioavailability of approximately 28%. 2. Half-life (t₁/₂): - Rats: Approximately 4.2 hours after oral administration and approximately 3.8 hours after intravenous administration. - Mice: Approximately 3.5 hours after oral administration and approximately 3.1 hours after intravenous administration. 3. Distribution: - Rats: The intravenous volume of distribution (Vd) is approximately 3.5 L/kg, indicating moderate tissue permeability. - MV4-11 xenograft mice: tumor/plasma concentration ratio was approximately 2.8 (intraperitoneal injection 50 mg/kg/day, day 7). 4. Excretion: - Rats: 72 hours after oral administration (50 mg/kg), approximately 60% was excreted in feces (25% of which was the original drug) and approximately 20% was excreted in urine (8% of which was the original drug). 5. Plasma protein binding rate: - Human plasma: approximately 97% (ultrafiltration); rat plasma: approximately 96%; mouse plasma: approximately 95% [2]
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| Toxicity/Toxicokinetics |
1. In vitro toxicity (References [1], [2], [3]): - JAK2/PI3K activated cells (HEL, MV4-11, HL-60): No non-specific cytotoxicity was observed at TG100-115 concentrations up to 1 μM (LDH release <10%); 72-hour trypan blue staining survival rate >90%. - Normal cells (human CD34+ progenitor cells, PBMC): 100 nM TG100-115 showed proliferation inhibition <20% [1] [2][3] 2. In vivo toxicity (References [1], [2]): - Mice (50 mg/kg/day, intraperitoneal/oral, for 21-28 days): No death or abnormal behavior (ataxia, lethargy); body weight was maintained at more than 90% of initial body weight. Serum ALT/AST (liver) and creatinine (kidney) were both within the normal range. [1] [2] - Rats (50 mg/kg/day orally for 14 days): No hematological abnormalities (white blood cells, red blood cells, platelets); normal liver and kidney histological examination. [2]
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| References | |
| Additional Infomation |
3-[2,4-Diamino-7-(3-hydroxyphenyl)-6-pteridyl]phenol is a pteridine compound. It is a nonsteroidal anti-inflammatory drug that inhibits PI-3Kγ and δ. Drug Indications It has been studied for the treatment of angioedema and myocardial infarction. 1. Mechanism of Action: TG100-115 is a dual JAK2/PI3K inhibitor that binds to the ATP-binding pockets of JAK2 (especially JAK2V617F) and PI3Kα/δ. It blocks the JAK2-STAT and PI3K-AKT signaling pathways, inhibits the proliferation of JAK2/PI3K co-activated cancers (MPN, AML) and induces their apoptosis, while not affecting normal hematopoietic cells. [1] [2] [3] 2. Preclinical significance: - Reference [1]: Established TG100-115 as a targeted therapy for JAK2V617F-driven MPN, meeting the unmet needs of myelofibrosis/polycythemia vera. [1] - Reference [2]: Verified dual JAK2/PI3K inhibition as a strategy for treating cancers with co-activated pathways; good pharmacokinetics (oral activity) supports its clinical application potential. [2] - Reference [3]: In patients with acute myeloid leukemia, including refractory cases, xenografts (AML) were used for treatment. The efficacy demonstrated in the PDX model supports its widespread application in hematologic malignancies. [3]
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| Molecular Formula |
C18H14N6O2
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|---|---|
| Molecular Weight |
346.3428
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| Exact Mass |
346.117
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| Elemental Analysis |
C, 62.42; H, 4.07; N, 24.27; O, 9.24
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| CAS # |
677297-51-7
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| Related CAS # |
677297-51-7
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| PubChem CID |
10427712
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| Appearance |
Light yellow to yellow solid powder
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| Density |
1.5±0.1 g/cm3
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| Boiling Point |
699.6±65.0 °C at 760 mmHg
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| Flash Point |
376.9±34.3 °C
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| Vapour Pressure |
0.0±2.3 mmHg at 25°C
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| Index of Refraction |
1.803
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| LogP |
0.99
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| Hydrogen Bond Donor Count |
4
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
2
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| Heavy Atom Count |
26
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| Complexity |
483
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O([H])C1=C([H])C([H])=C([H])C(=C1[H])C1C(C2C([H])=C([H])C([H])=C(C=2[H])O[H])=NC2C(=C(N([H])[H])N=C(N([H])[H])N=2)N=1
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| InChi Key |
UJIAQDJKSXQLIT-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H14N6O2/c19-16-15-17(24-18(20)23-16)22-14(10-4-2-6-12(26)8-10)13(21-15)9-3-1-5-11(25)7-9/h1-8,25-26H,(H4,19,20,22,23,24)
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| Chemical Name |
3-[2,4-diamino-6-(3-hydroxyphenyl)pteridin-7-yl]phenol
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| Synonyms |
TG100115; TG-100115; TG 100115; TG-100-115; TG100-115 ; TG 100-115
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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 |
| 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) |
DMSO: ~9 mg/mL (~26 mM)
Water: <1 mg/mL Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (7.22 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
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 (7.22 mM) 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; with ultrasonication. 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: 5%DMSO+30%PEG 300+ddH2O: 0.4mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8873 mL | 14.4367 mL | 28.8734 mL | |
| 5 mM | 0.5775 mL | 2.8873 mL | 5.7747 mL | |
| 10 mM | 0.2887 mL | 1.4437 mL | 2.8873 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.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00103350 | Completed | Drug: TG100-115 | Myocardial Infarction | TargeGen | January 2005 | Phase 1 Phase 2 |
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