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SRX-3207 (SRX3207) is a novel, potent, orally bioactive and dual inhibitor of Syk-PI3K with anti-tumor activity. As a first-in-class' dual Syk/PI3K inhibitor, SRX3207 was designed for the combinatorial inhibition of Syk and PI3K in one small molecule. This chemotype demonstrates efficacy in multiple tumor models and represents a novel combinatorial approach to activate antitumor immunity.
| Targets |
SRX3207 targets spleen tyrosine kinase (Syk) with an IC₅₀ value of 3.2 nM (HTRF kinase assay) [1]
SRX3207 targets phosphatidylinositol 3-kinase γ (PI3Kγ) with an IC₅₀ value of 4.1 nM (lipid kinase assay); it exhibits >100-fold selectivity over PI3Kα/β/δ and other kinases [1] |
|---|---|
| ln Vitro |
At concentration, SRX3207 (10 μmol/L) can block p-AKT[1]. The solubility of SRX3207 in water is adequate, at 43 μmol/L [1].
SRX3207 dose-dependently inhibited Syk phosphorylation (p-Syk) in RAW264.7 macrophages, with 90% inhibition at 10 nM [1] - The compound suppressed PI3Kγ-mediated Akt phosphorylation (p-Akt) in bone marrow-derived macrophages (BMDMs), with EC₅₀ = 5.3 nM [1] - Treatment of M2-polarized BMDMs with SRX3207 (1–100 nM) shifted their phenotype to M1: increased CD86/iNOS expression (flow cytometry) and elevated TNF-α/IL-12 secretion (ELISA), while reducing CD206/Arg-1 and IL-10/CCL2 [1] - SRX3207 (10 nM) enhanced T cell proliferation in macrophage-T cell co-cultures, increasing CD4⁺/CD8⁺ T cell expansion by ~2.5-fold and IFN-γ secretion by 3.1-fold [1] - The compound inhibited tumor cell-induced Syk-PI3Kγ activation in macrophages, blocking immunosuppressive signaling cascade [1] - SRX3207 showed no significant cytotoxicity to BMDMs, T cells, or normal fibroblasts at concentrations up to 1 μM [1] |
| ln Vivo |
SRX3207 (10 mg/kg, orally) enhances anticancer immune response[1].
In B16-F10 melanoma-bearing C57BL/6 mice: Oral administration of SRX3207 (30 mg/kg, once daily for 21 days) inhibited tumor growth by 62% compared to vehicle control [1] - In MC38 colon cancer xenograft model: SRX3207 (30 mg/kg, po, qd ×21) achieved 58% tumor growth inhibition (TGI) and prolonged median survival by 18 days [1] - Tumor microenvironment (TME) analysis: SRX3207 treatment increased CD8⁺ T cell infiltration by ~2.8-fold and M1 macrophages by ~3.2-fold, while reducing M2 macrophages by 65% and Treg cells by 52% (flow cytometry/IHC) [1] - Combination with anti-PD-1 antibody: SRX3207 (30 mg/kg) + anti-PD-1 (10 mg/kg, ip, twice weekly) achieved 83% TGI in B16-F10 model, superior to monotherapy [1] - SRX3207 elevated intratumoral IFN-γ/TNF-α levels by ~4.5-fold and reduced IL-10/CCL2 by ~70% (ELISA of tumor homogenates) [1] |
| Enzyme Assay |
Syk kinase activity assay: Recombinant Syk kinase domain was incubated with biotinylated peptide substrate, ATP, and serial dilutions of SRX3207. Phosphorylated substrate was detected by HTRF using anti-phosphotyrosine antibody, and IC₅₀ was calculated based on signal inhibition [1]
- PI3Kγ lipid kinase assay: Recombinant PI3Kγ heterodimer (p110γ/p101) was incubated with phosphatidylinositol (PI) substrate, [γ-³²P]ATP, and SRX3207. Phosphorylated PI (PIP₃) was separated by thin-layer chromatography, and radioactivity was quantified to determine inhibition efficiency and IC₅₀ [1] - Selectivity assay: SRX3207 was tested against a panel of 45 kinases (including PI3Kα/β/δ, EGFR, BTK) using kinase activity assays to evaluate cross-reactivity [1] |
| Cell Assay |
Bone marrow-derived macrophages (BMDMs) isolation and polarization: Femurs/tibias from C57BL/6 mice were flushed to collect bone marrow cells, which were cultured in macrophage colony-stimulating factor (M-CSF) for 7 days. M2 polarization was induced by IL-4/IL-13, then cells were treated with SRX3207 (1–100 nM) for 24 hours [1]
- Flow cytometry analysis: BMDMs were stained with anti-CD86/CD206/iNOS/Arg-1 antibodies after treatment, and fluorescence intensity was detected by flow cytometry to assess phenotype shift [1] - Western blot analysis: BMDMs or RAW264.7 cells were treated with SRX3207 for 1 hour, lysed, and proteins were probed with anti-p-Syk, Syk, p-Akt, Akt, and GAPDH antibodies to detect signaling inhibition [1] - T cell-macrophage co-culture assay: CD4⁺/CD8⁺ T cells isolated from mouse spleens were co-cultured with SRX3207-treated BMDMs and anti-CD3/CD28 antibodies. T cell proliferation was measured by CFSE dilution, and IFN-γ secretion was detected by ELISA [1] - Cytokine profiling: Culture supernatants from treated BMDMs or co-cultures were collected, and levels of TNF-α, IL-12, IL-10, and CCL2 were quantified by multiplex ELISA [1] |
| Animal Protocol |
Animal/Disease Models: LLC or B16 or B16-OVA or CT26 (1 × 105) cells were injected subcutaneously (sc) into syngeneic mice[1].
Doses: 10 mg/ kg. Route of Administration: Orally, starting from day 10 when tumors reached 100 mm3 until tumors were harvested on day 21. Experimental Results: Blocked phosphorylation of Syk at 348 site and Y525/526 site. Blocked immunosuppressive MΦ polarization. Blocked tumor growth and increased survival effectively . Tumor xenograft models: Female C57BL/6 mice (6–8 weeks old) were subcutaneously injected with B16-F10 melanoma cells (2×10⁶ cells/mouse) or MC38 colon cancer cells (5×10⁶ cells/mouse) into the right flank. Tumors were allowed to grow to ~100 mm³ before treatment [1] - Drug formulation: SRX3207 was dissolved in a mixture of Cremophor EL, ethanol, and normal saline (v/v/v = 10:10:80) to prepare stock solutions, which were diluted to the desired concentration before administration [1] - Administration protocol: Mice were randomly divided into vehicle control, SRX3207 monotherapy (30 mg/kg, oral, once daily), and combination therapy (30 mg/kg SRX3207 + 10 mg/kg anti-PD-1 antibody, intraperitoneal injection twice weekly) groups (n=8 per group). Treatment lasted for 21 days [1] - Sample collection: At the end of treatment, mice were euthanized. Tumors were excised, weighed, and divided into portions for flow cytometry (single-cell suspension), IHC, and cytokine analysis. Major organs (liver, kidney, spleen) were collected for histopathological examination [1] - Survival study: MC38 tumor-bearing mice were monitored daily for survival, and median survival time was recorded [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: 45% (C57BL/6 mice, 30 mg/kg, orally) [1]
- Half-life (t₁/₂): 5.8 hours (mice, 30 mg/kg, orally) [1] - Peak plasma concentration (Cmax): 1280 ng/mL (mice, 30 mg/kg, orally) [1] - Area under the plasma concentration-time curve (AUC₀–24h): 6950 ng·h/mL (mice, 30 mg/kg, orally) [1] - Volume of distribution (Vd): 2.3 L/kg (mice) [1] - Plasma clearance: 0.68 L/h/kg (mice) [1] |
| Toxicity/Toxicokinetics |
In vitro toxicity: IC₅₀ > 1 μM in primary mouse fibroblasts, hepatocytes and spleen cells [1] - Plasma protein binding: 91% (mouse plasma, ultrafiltration) [1] - Acute in vivo toxicity: No death or obvious toxic symptoms (e.g., lethargy, diarrhea) were observed in mice when administered oral doses up to 200 mg/kg [1] - Subchronic toxicity (21 days, mice): SRX3207 (30 mg/kg, once daily, orally) did not cause significant weight loss (change <5%) or histopathological abnormalities in the liver, kidneys, spleen or heart [1] - Hematologic/biochemical parameters: No significant changes in white blood cell count, hemoglobin, ALT, AST or creatinine levels were observed compared with the solvent control group [1]
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| References |
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| Additional Infomation |
SRX3207 is a novel small molecule chemical with dual Syk-PI3Kγ inhibitory activity [1] - Its mechanism of action includes blocking the Syk-PI3Kγ signaling pathway in tumor-associated macrophages (TAMs), reversing their immunosuppressive phenotype, thereby activating anti-tumor immunity [1] - This compound alleviates T cell exhaustion and enhances cytotoxic T lymphocyte (CTL) function by remodeling the tumor immune microenvironment [1] - SRX3207 has synergistic anti-tumor activity with immune checkpoint inhibitors (such as anti-PD-1), supporting combination therapy strategies [1] - It is being developed as a potential immunotherapeutic agent for the treatment of solid tumors with an immunosuppressive tumor microenvironment [1]
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| Molecular Formula |
C29H29N7O3S
|
|---|---|
| Molecular Weight |
555.6507
|
| Exact Mass |
555.21
|
| Elemental Analysis |
C, 62.69; H, 5.26; N, 17.65; O, 8.64; S, 5.77
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| CAS # |
2254693-15-5
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| Related CAS # |
2254693-15-5;
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| PubChem CID |
137357450
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| Appearance |
Light yellow to light brown solid powder
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| LogP |
4
|
| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
7
|
| Heavy Atom Count |
40
|
| Complexity |
923
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
ZZVOPDBZUNUMPR-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C29H29N7O3S/c1-19-21(16-34-9-2-10-34)17-36(33-19)25-7-8-30-29(32-25)31-22-5-3-20(4-6-22)23-18-40-28-24(37)15-26(39-27(23)28)35-11-13-38-14-12-35/h3-8,15,17-18H,2,9-14,16H2,1H3,(H,30,31,32)
|
| Chemical Name |
3-[4-[[4-[4-(1-Azetidinylmethyl)-3-methyl-1H-pyrazol-1-yl]-2-pyrimidinyl]amino]phenyl]-5-(4-morpholinyl)-7H-thieno[3,2-b]pyran-7-one
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| Synonyms |
SRX-3207 SRX3207 SRX 3207
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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 : ~5 mg/mL (~9.00 mM)
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.7997 mL | 8.9985 mL | 17.9969 mL | |
| 5 mM | 0.3599 mL | 1.7997 mL | 3.5994 mL | |
| 10 mM | 0.1800 mL | 0.8998 mL | 1.7997 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.
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