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Purity: ≥98%
Pilaralisib analog (XL-147 analog, SAR-245408) is novel, selective, potent, orally bioavailable and reversible small molecule inhibitor of Class 1 PI3K (phosphatidylinositol 3 kinase) family of kinases with potential anticancer activity.
| Targets |
PI3Ky (IC50 = 23 nM); PI3Kδ (IC50 = 36 nM); PI3Kα (IC50 = 39 nM); PI3Kβ (IC50 = 383 nM)
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|---|---|
| ln Vitro |
XL147 inhibits class I PI3K isoforms in an ATP-competitive manner. Treatment with XL147 eliminates AKT and S6 phosphorylation in a panel of HER2-overexpressing human breast cancer cell lines, but it also promotes the expression and phosphorylation of HER3 and other RTKs. The HER2 tyrosine kinase maintains the phosphorylation of HER3 in HER2+ cells, which results in a partial recovery of phosphorylated AKT (pAKT), limiting the antitumor effect of XL 147. Furthermore, transtuzumab or lapatinib therapy or HER3 knockdown sensitize HER2+ breast cancer cells to XL147 in vitro and in vivo. All tested cell lines, including BT474, HCC1937, and others, exhibit dose-dependent inhibition of monolayer growth in response to treatment with XL147. Inhibition of cell proliferation is XL147's main effect. At a 20 M concentration, XL147 induces cell death. PI3K is dose-dependently inhibited after receiving treatment with XL147. A decrease in cyclin D1 and pRB and an increase in the CDK inhibitor p27KIPI are caused by XL147, which is consistent with the inhibition of cell proliferation. However, there is no discernible change in the levels of total or cleaved poly (ADP-ribose) polymerase (PARP). A dose-dependent decrease in pAKTS473/T308 and pS6S240/244 results from XL147 treatment. Unexpectedly, XL147 also causes an increase in the levels of total HER3 and/or pHER3Y1289. When PI3K is inhibited in HER2-overexpressing cells, several receptor tyrosine kinases, including HER3, are then expressed and phosphorylated more strongly. HER3, InsR, IGF1R, and FGFR2 mRNAs are not induced when PI3K is inhibited when FoxO1 and FoxO3a transcription factors are knocked down. Trastuzumab or lapatinib cotreatment or HER3 siRNA knockdown in HER2+ cells both increase XL147-induced cell death and pAKT and pS6 inhibition.[1]
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| ln Vivo |
Athymic mice with BT474 xenografts are randomly treated with XL147, lapatinib, trastuzumab, or XL147 plus each HER2 antagonist.Trastuzumab was the only medication to cause a complete tumor regression in one of eight mice, significantly inhibiting tumor growth with each monotherapy. Both combinations are better than the individual medications when taken alone. Notably, three out of eight mice receive a full tumor response from the combination of trastuzumab and XL147, but not from the combination of lapatinib and XL147. In any of the treatment arms, there is no overt drug-related toxicity. More effectively than any other treatment, XL147 combined with trastuzumab inhibits pHER3.Nuclear pAKT is lower in tumors treated with XL147 plus lapatinib or XL147 plus trastuzumab compared to tumors treated with single agents, which is in excellent agreement with differences in tumor growth among treatment arms. Only XL147 has been statistically proven to statistically reduce nuclear pAKT levels among the three individual drugs. Cytoplasmic pAKT levels do not change in any discernible way. To effectively inhibit the PI3K/AKT pathway's signaling output, HER2 and PI3K must be inhibited simultaneously in HER2-dependent xenografts.[1]
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| Enzyme Assay |
Pilaralisib analog, also known as XL147 analogue, is a Class 1 PI3K kinase family inhibitor, and is a n orally bioavailable small molecule, targeting the class I phosphatidylinositol 3 kinase (PI3K) family of lipid kinases, with potential antineoplastic activity. Class 1 PI3K kinase family inhibitor XL147 reversibly binds to class 1 PI3Ks in an ATP-competitive manner, inhibiting the production of the secondary messenger phosphatidylinositol-3,4,5-trisphosphate (PIP3) and activation of the PI3K signaling pathway; this may result in inhibition of tumor cell growth and survival in susceptible tumor cell populations. Activation of the PI3K signaling pathway is frequently associated with tumorigenesis.
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| Cell Assay |
Cells (BT474, HCC1937 et al) are seeded in 100-mm dishes in media containing 2.5% FBS with or without XL147. After 3 days, detached and adherent cells are pooled, fixed, and labeled with propidium iodide by using the APO-BrdU kit. Labeled cells are analyzed using the Becton Dickinson FACSCalibur system.
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| Animal Protocol |
Athymic female mouse bearing BT474 cells
100 mg/kg Orogastric gavage |
| References |
| Molecular Formula |
C21H16N6O2S2
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|---|---|
| Molecular Weight |
448.521
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| Exact Mass |
540.13
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| Elemental Analysis |
C, 55.50; H, 4.66; Cl, 6.55; N, 15.53; O, 11.83; S, 5.93
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| CAS # |
956958-53-5
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| Related CAS # |
956958-53-5; 934526-89-3
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| Appearance |
Solid powder
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| SMILES |
O=S(C1=CC=C(C)C=C1)(NC2=NC3=CC=CC=C3N=C2NC4=CC5=NSN=C5C=C4)=O
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| InChi Key |
QINPEPAQOBZPOF-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C25H25ClN6O4S/c1-25(2,27)24(33)28-15-7-6-8-17(13-15)37(34,35)32-23-22(29-19-9-4-5-10-20(19)30-23)31-21-14-16(36-3)11-12-18(21)26/h4-14H,27H2,1-3H3,(H,28,33)(H,29,31)(H,30,32)
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| Chemical Name |
2-amino-N-(3-(N-(3-((2-chloro-5-methoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylpropanamide.
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| Synonyms |
Pilaralisib; L147; XL-147; XL 147; SAR 245408; SAR245408; SAR-245408
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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: ~3 mg/mL (6.7 mM)
Water: <1 mg/mL (slightly soluble or insoluble) Ethanol: <1 mg/mL |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (5.57 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 system 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 (5.57 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. Solubility in Formulation 3: ≥ 2.5 mg/mL (5.57 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 corn oil and mix evenly. Solubility in Formulation 4: 30% PEG400+0.5% Tween80+5%Propylene glycol: 15mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2296 mL | 11.1478 mL | 22.2955 mL | |
| 5 mM | 0.4459 mL | 2.2296 mL | 4.4591 mL | |
| 10 mM | 0.2230 mL | 1.1148 mL | 2.2296 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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Chakrabarty A, et al. Proc Natl Acad Sci U S A, 2011, 1-6. |
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