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| Targets |
PI3Kα[1].
STX-478 selectively targets mutant forms of PI3Kα, including common helical- and kinase-domain mutations such as the H1047R variant. It exhibits strong efficacy against these prevalent mutants with an IC50 value of 9.4 nmol/L for the H1047R variant. Importantly, it shows 14-fold greater selectivity for mutant PI3Kα over the wild-type form. This high selectivity for oncogenic mutants while sparing the wild-type enzyme is a key feature, as it aims to improve therapeutic response and reduce metabolic dysfunction. |
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| ln Vitro |
For MCF10A cells with the H1047R kinase domain mutation, STX-478 (0-10,000 nM; 1 h) exhibits selectivity [1].
In vitro, STX-478 demonstrates potent inhibitory activity against mutant PI3Kα, with an IC50 of 9.4 nmol/L for the H1047R mutant. It is highly selective, exhibiting 14-fold greater potency against mutant forms compared to the wild-type enzyme. This selectivity profile is crucial for minimizing off-target effects and improving the therapeutic window. The compound's activity is assessed using biochemical kinase assays and cell-based proliferation assays in cancer cell lines harboring PI3Kα mutations. |
| ln Vivo |
In a mouse CAL-33 xenograft model, STX-478 (30, 100 mg/kg; po; once daily for 28 days) suppresses tumor growth in a dose-dependent manner[1].
In vivo, STX-478 has demonstrated robust and durable tumor regression in preclinical models, including those with brain metastases. Its ability to penetrate the central nervous system (CNS) makes it particularly valuable for treating tumors that have metastasized to the brain. The compound spares metabolic dysfunction and improves therapeutic response in PI3Kα-mutant xenografts, supporting its potential as a precision oncology therapeutic for PI3K-driven tumors. |
| Enzyme Assay |
Cell-free assays for STX-478 typically involve measuring its inhibitory activity against wild-type and mutant PI3Kα using biochemical kinase assays. The IC50 value of 9.4 nmol/L against the H1047R mutant is determined by measuring the phosphorylation of a lipid substrate, such as PIP2, in the presence of varying concentrations of the inhibitor. Selectivity is assessed by comparing the compound's potency against a panel of PI3Kα mutants versus the wild-type enzyme. These assays are essential for characterizing the compound's potency and allosteric mechanism of action.
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| Cell Assay |
Immunofluorescence[1]
Cell Types: MCF10A cells Tested Concentrations: 0-10,000 nM Incubation Duration: 1 h Experimental Results: Targeted the MCF10A cells (with the H1047R kinase domain mutation). In vitro cellular assays are conducted to evaluate the functional activity of STX-478 in cancer cell lines harboring PI3Kα mutations. Cells are treated with the compound, and cell viability and proliferation are measured to assess anti-proliferative effects. PI3K/AKT pathway inhibition is confirmed by measuring the phosphorylation of downstream effectors such as AKT. These assays confirm that STX-478 effectively and selectively blocks signaling in mutant PI3Kα-driven cells. |
| Animal Protocol |
Animal/Disease Models: Female BALB/c nude mice (CAL-33 xenograft model)[1].
Doses: 30, 100 mg/kg Route of Administration: Oral administration Experimental Results: demonstrated a dose-dependent reduction in tumor volume. In vivo animal experiments typically involve xenograft models of cancers with PI3Kα mutations, including those with brain metastases. Mice bearing these tumors are administered STX-478 orally, given its oral bioavailability. Tumor growth is monitored over time to assess the compound's efficacy in causing tumor regression. The compound's CNS penetration is evaluated to confirm its ability to reach and inhibit tumors in the brain. |
| ADME/Pharmacokinetics |
The pharmacokinetic properties of STX-478 are characterized by its oral bioavailability and ability to penetrate the blood-brain barrier (BBB). It has a molecular weight of 401.29 and a molecular formula of C16H12F5N5O2. The compound is soluble in DMSO at 80 mg/mL. Its favorable PK properties support its use in vivo and its potential as a therapeutic agent for cancers, including those with CNS involvement.
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| Toxicity/Toxicokinetics |
The toxicity profile of STX-478 is expected to be favorable due to its selectivity for mutant PI3Kα over the wild-type enzyme. By sparing wild-type PI3Kα, the compound aims to reduce off-target effects and metabolic dysfunction commonly associated with pan-PI3K inhibitors. It is intended for research use only and is not for human consumption. Preclinical studies have supported its safety profile, but detailed toxicology data are not publicly available.
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| References | |
| Additional Infomation |
STX-478, a mutant-selective PI3K-α H1047X inhibitor, is a class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic subunit α (phosphatidylinositol 3-kinase α; PIK3CA; PI3K p110α) mutant-selective inhibitor with high oral bioavailability and blood-brain barrier penetration, exhibiting potential antitumor activity. After oral administration, STX-478 selectively targets and allosterically binds to the PIK3CA mutant PIK3CA H1047X, thereby inhibiting its activity. This prevents PIK3CA H1047X-mediated activation of the PI3K/Akt (protein kinase B)/mTOR pathway. This leads to apoptosis and inhibits the growth of tumor cells expressing the PIK3CA H1047X mutation. By specifically targeting the PIK3CA H1047X mutation, STX-478 may be more effective and less toxic than other non-mutation-specific PI3K-α inhibitors. PI3K/Akt/mTOR pathway dysregulation is common in solid tumors, leading to tumor cell growth, survival, and resistance to chemotherapy and radiotherapy. PIK3CA is one of the most commonly mutated oncogenes, encoding the p110-α catalytic subunit of class I PI3K. STX-478 can cross the blood-brain barrier (BBB).
STX-478 is a promising candidate for precision oncology, making it a valuable tool in cancer research focused on PI3K-driven tumors. Its unique allosteric, mutant-selective mechanism offers a potential advantage over ATP-competitive inhibitors by reducing off-target effects. The compound is being investigated for the treatment of breast cancer and other solid tumors. Its ability to penetrate the CNS also positions it as a potential therapy for brain metastases. |
| Molecular Formula |
C16H12F5N5O2
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|---|---|
| Molecular Weight |
401.290800094604
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| Exact Mass |
401.091
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| CAS # |
2883540-92-7
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| PubChem CID |
166532451
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| Appearance |
White to off-white solid powder
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| LogP |
2.5
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
10
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
560
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC1=C(OC2=C1C=C(C=C2F)F)[C@H](C(F)(F)F)NC(=O)NC3=CN=C(N=C3)N
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| InChi Key |
LGPNQALKGDDVBD-CYBMUJFWSA-N
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| InChi Code |
InChI=1S/C16H12F5N5O2/c1-6-9-2-7(17)3-10(18)12(9)28-11(6)13(16(19,20)21)26-15(27)25-8-4-23-14(22)24-5-8/h2-5,13H,1H3,(H2,22,23,24)(H2,25,26,27)/t13-/m1/s1
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| Chemical Name |
1-(2-aminopyrimidin-5-yl)-3-[(1R)-1-(5,7-difluoro-3-methyl-1-benzofuran-2-yl)-2,2,2-trifluoroethyl]urea
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| Synonyms |
Tersolisib; STX-478; STX478
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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: 250 mg/mL (622.99 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 | 2.4920 mL | 12.4598 mL | 24.9196 mL | |
| 5 mM | 0.4984 mL | 2.4920 mL | 4.9839 mL | |
| 10 mM | 0.2492 mL | 1.2460 mL | 2.4920 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.
Link: https://clinicaltrials.gov/ct2/show/NCT05768139
Conditions:Breast Cancer|Solid Tumors, AdultProducts are for research use only; We do not sell to patients
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