TP-18
TP-18 is a potent and orally active dual EP2/EP4 antagonist with IC50 values of 9.5 nM (EP2) and 3.3 nM (EP4). TP-18 effectively depletes a highly immunosuppressive VSIG4high tumor-associated macrophage (TAM) subset and enhances cytotoxic CD8+ T cell-mediated colorectal cancer (CRC) tumor elimination. TP-18 dampens the expression of VSIG4 by blunting EP2/EP4-Gαs-PKA signaling. TP-18 enhances the sensitivity of anti-PD-1 therapy in CRC mouse models and in patient-derived tumor immune organoids. TP-18 can be used to study colorectal cancer.
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- Fòrmula: C25H25FN4O3
- Peso molecular:448.49
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EP2 9.5 nM (IC50) |
EP4 3.3 nM (IC50) |
TP-18 (30 min) exhibits strong antagonistic capacity against human EP2 and EP4 with half-maximal inhibitory concentration (IC50) values of 9.5 and 3.3 nM, respectively in HEK293 cells in GloSensor cAMP assay[1].
TP-18 (24 h) exhibits potent antagonistic activity against human EP2 and EP4 in a CRE-luciferase assay, with IC50 values of 16.6 nM and 4.9 nM in CHO cells, respectively[1].
TP-18 (1 h) potently suppresses PGE2-induced β-arrestin recruitment in CHO-EP2 cells and CHO-EP4 cells with IC50 values of 11.1 and 10.5nM, respectively[1].
TP-18 (15 min) exhibits robust antagonism against EP2 and EP4 in a Gα16-mediated calcium flux assay, with IC50 values of 9.9 nM and 5.6 nM, respectively, and >1,000-fold selectivity over EP1 and EP3 receptors (IC50 > 10,000 nM for both) inCHO-Gα16 cells[1].
GPCRs (15 min) is not influenced by TP-18 (IC50 > 10,000 nM) in CHO-Gα16 cells[1].
TP-18 (30 min) induces a rightward shift of the PGE2 dose-response curves in HEK293-EP2 and HEK293-EP4 cells without affecting the maximal cAMP level, with Schild-plot analysis yielding pA2 values of 8.5 (slope = 1.0) and 8.9 (slope = 1.0), respectively in the GloSensor cAMP assay[1].
TP-18 (1 μM; 24 h) impairs expression of immune checkpoint molecule VSIG4 in TAMs through inactivating Gαs-PKA-CREB signaling in PMs and TAMs[1].
TP-18 (1 μM; 24 h) nearly completely abrogates PGE2-induced VSIG4 expression in PMs isolated from WT C57BL/6J mice[1].
TP-18 (1 μM; 24 h) confers a significant reduction in PGE2-induced up-regulation of p-CREB and VSIG4 in TAMs isolated from CT26 tumors via magnetic particles[1].
TP-18 (10 μM; 7 days) as monotherapy effectively increases tumor-infiltrating activated CD8⁺GZMB⁺ T cells, reduces immunosuppressive CD11b⁺VSIG4⁺ cells, and induces apoptosis in patient-derived tumor immune organoids (PDTIOs); these effects are further augmented when TP-18 is combined with anti-PD-1[1].
TP-18 (10 μM; 7 days) in combination with anti-PD-1 elicits superior CD8⁺ T cell activation and tumor cell cytotoxicity compared with TP-18 or anti-PD-1 alone[1].
TP-18 (72 h) does not directly influence the cell viability of murine cancer cells (CT26, MC38, and LLC) and human cancer cells (SW620, HCT116, and A549) at 100 μM[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
TP-18 (25-150 mg/kg; p.o.; once a day; 26 days) triggers CD8+ T cell-mediated anti-tumor immune response to promote tumor regression in CT26-bearing BALB/c mice[1].
TP-18 (50 mg/kg; p.o.; once a day) exhibits robust anti-tumor effects in both MC38 CRC model and lewis lung carcinoma (LLC) model[1].
TP-18 (50 mg/kg; p.o.; once a day; 15 days) fails to inhibit tumor growth in CT26-inoculated immunodeficient BALB/c nude mice, highlighting the requirement of a functional immune system for TP-18’s anti-tumor effect[1].
TP-18 (50 mg/kg; p.o.; once a day) depletes immunosuppressive VSIG4⁺ TAMs to boost CD8⁺ T cell response, as CD8⁺ T cell depletion nearly completely abrogates its anti-tumor effect in CT26-bearing BALB/c mice, indicating that its tumor-regressive activity is critically dependent on CD8⁺ T cell-mediated immunity[1].
TP-18 (50 mg/kg; p.o.; once a day; 17 days) nearly completely loses its anti-tumor effect in the BALB/c mice in the CT26 model upon clodronate-liposome-mediated macrophage depletion[1].
TP-18 (50 mg/kg; p.o.; once a day; 30 days) overcomes primary and acquired resistance to anti-PD-1 therapy in Azoxymethane (AOM) (HY-111375)/ Dextran Sulfate Sodium Salt (DSS) (HY-116282)-induced colorectal cancer mice models[1].
TP-18 (50 mg/kg; p.o.; once a day; 4 weeks) renders anti-PD-1 therapy responsiveness in ApcMin/+ mice, a classic genetic mouse intestinal tumor model with MSS genotype and intrinsic resistance to ICB immunotherapies[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:Immune-competent BALB/c mice (6-8 weeks) were inoculated with CT26 and MC38 tumors.[1]
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Dosage:25 mg/kg; 50 mg/kg; 100 mg/kg; 150 mg/kg
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Administration:p.o.; once a day
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Result:Impaired tumor growth as reflected by reduced tumor volumes compared with vehicle control significantly, with no significant alterations in body weight.
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Animal Model:Immune-competent BALB/c mice were inoculated with CT26 and MC38 tumors.[1]
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Dosage:50 mg/kg
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Administration:p.o.; once a day
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Result:Demonstrated superior anti-tumor efficacy compared to EP2i, EP4i, and celecoxib, exhibiting tumor growth inhibition rates of 87.0%, 55.6%, 65.0%, and 60.1%, respectively, under the same dosage.
Decreased the presence of TAMs profoundly.
Inhibited CD8⁺ T cell proliferation to a lesser extent than those from vehicle-treated mice.
Markedly restored CD8+ T cell proliferation and GZMB expression, counteracting the immunosuppressive capacity of PGE2 on macrophages.
Down-regulated a panel of immune checkpoint molecules compared with control-vehicle-treated group.
Reduced the expression of Vsig4 among these immune checkpoint moleculesmost significantly.
Led to a significant decrease of VSIG4 protein expression in TAMs, accompanied by a reduced proportion of VSIG4high TAM Showed no additive anti-tumor effect when combined with anti-VSIG4 antibody in CT26 tumor-bearing mice, consistent with TP-18 acting through the VSIG4 pathway.
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Animal Model:Immune-competent BALB/c mice were inoculated with CT26 and MC38 tumors.[1]
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Dosage:50 mg/kg
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Administration:p.o.; once a day; 21 days
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Result:Increased proportion of tumor-infiltrating CD8+ T cells, GZMB+CD8+ T cells, and interferon-γ (IFNγ+) CD8+ T cells in TP-18-treated mice, compared with vehicle-treated mice.
Elevated proportion of CD8+ T cells and GZMB+CD8+ cells significantly.
Up-regulated the expression of T cell activation biomarkers (Cd27, Cd28, Cd69, Cd122, and Cd132) and T cell cytotoxic effector molecules (Gzmb, Ifng, Prf1, and Tnf).
Indicated an enrichment of T cell response in TP-18-treated tumors, compared with vehicle-treated tumors.
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Animal Model:6-8-week-old female BALB/c mice were given a single intraperitoneal injection of AOM (10 mg/kg), and after 5 days of rest, subjected to three cycles of 2.5% DSS in drinking water for 5 days followed by 2 weeks of regular water.[1]
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Dosage:50 mg/kg
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Administration:p.o.; once a day; 30 days
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Result:Had little or no effect on AOM/DSS-induced tumors with monotherapy compared with vehicle control.
Showed that the combination therapy was clearly superior to monotherapies.
Demonstrated that the combination therapy significantly increased the infiltration and activation of cytotoxic CD8+ T cells as compared with vehicle- or monotherapy-treated groups.
Showed that monotherapy or combination therapy caused a significant reduction in VSIG4high TAMs.
Showed that combination therapy was well tolerated, with no significant body weight changes observed during treatment.
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Animal Model:6-8-week-old female C57BL/6J mice were anesthetized with isoflurane, and after abdominal opening, CT26-luc-mCherry cells (5 × 105) were simultaneously injected subcutaneously and intrasplenically, followed by immediate splenectomy.[1]
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Dosage:50 mg/kg
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Administration:p.o.; once a day; 19 days
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Result:Suppressed the growth of both subcutaneous and liver tumors significantly.[1] Exhibited profound regression of both subcutaneous and liver tumors with significantly extended median survival times in mice administrated with TP-18 and anti-PD-1 combination therapy, relative to the TP-18 or anti-PD-1 monotherapies.
Augmented cytotoxic CD8+ T cell abundance and activation in both subcutaneous and liver tumors significantly in combined TP-18/anti-PD-1 therapy compared to anti-PD-1 therapy alone.
Reduced VSIG4high TAMs in TP-18 or TP-18/anti-PD-1 treated groups significantly.
Chemical Information
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Peso molecular 448.49
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Fòrmula C25H25FN4O3
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SMILES
CCOC1=CC(C2=NC=NC(NCCC3=C(NC4=C3C(C)=CC=C4F)C)=C2)=CC=C1C(O)=O
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Please store the product under the recommended conditions in the Certificate of Analysis.
Pureza y Documentación
Referencias
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
TP-18 Related Classifications
HY-184555 Related Classifications
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