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Pilaralisib (formerly XL-147; SAR-245408) is a novel, potent, orally bioavailable, ATP-competitive, selective and reversible inhibitor of class I PI3K (phosphatidylinositol 3-kinase) has been shown to have potential anticancer activity. It is less potent against PI3Kβand inhibits PI3Kα/δ/γ with an IC50 of 39 nM/36 nM/23 nM in cell-free assays. For the treatment of various cancers, including lymphoma, solid tumors, glioblastoma, and breast cancer, pilaralisib has been studied.
Physicochemical Properties
| Molecular Formula | C25H25CLN6O4S |
| Molecular Weight | 541.0218 |
| Exact Mass | 540.135 |
| Elemental Analysis | C, 55.50; H, 4.66; Cl, 6.55; N, 15.53; O, 11.83; S, 5.93 |
| CAS # | 934526-89-3 |
| Related CAS # | 934526-89-3;956958-53-5.; |
| PubChem CID | 56599306 |
| Appearance | Light yellow to yellow solid powder |
| LogP | 5.786 |
| Hydrogen Bond Donor Count | 4 |
| Hydrogen Bond Acceptor Count | 9 |
| Rotatable Bond Count | 8 |
| Heavy Atom Count | 37 |
| Complexity | 887 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C(C(C)(C)N)NC1C=C(S(NC2C(NC3C(Cl)=CC=C(OC)C=3)=NC3C(=CC=CC=3)N=2)(=O)=O)C=CC=1 |
| InChi Key | QINPEPAQOBZPOF-UHFFFAOYSA-N |
| 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) |
| Chemical Name | 2-amino-N-(3-(N-(3-((2-chloro-5-methoxyphenyl)amino)quinoxalin-2-yl)sulfamoyl)phenyl)-2-methylpropanamide. |
| Synonyms | XL147; XL 147; Pilaralisib; SAR 245408; SAR245408; SAR-245408; XL-147 |
| HS Tariff Code | 2934.99.9001 |
| 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) |
Biological Activity
| Targets | PI3Kα (IC50 = 39 nM); PI3Kβ (IC50 = 383 nM); PI3Kδ (IC50 = 36 nM); PI3Kγ (IC50 = 23 nM); Vps34 (IC50 = 6974 nM); DNA-PK (IC50 = 4750 nM) |
| ln Vitro | Pilaralisib exhibits cytotoxic activity in Pediatric Preclinical Testing Program (PPTP) cell lines, with a median relative IC50 of 10.9 mM (interquartile range, 2.7 to 24.5 mM).[2] |
| ln Vivo | Pilaralisib (100 mg/kg, p.o.) inhibits the growth of solid glioma xenografts in BALB/c nu/nu mice. With a toxicity rate of only 0.7% in the treated groups, pilaralisib is well tolerated and is comparable to what was seen in the control animal population. [2] Pilaralisib (100 mg/kg, p.o.) significantly slows tumor growth in athymic female mice while posing minimal drug-related side effects. [3] |
| Enzyme Assay | Using luciferase-luciferin-coupled chemiluminescence, kinase activity for PI3K isoforms is quantified as the proportion of ATP consumed after the kinase reaction, with ATP concentrations roughly equal to the Km for each individual kinase. Test compounds, ATP, and kinase are combined in a 20 μL volume to start kinase reactions. The final enzyme concentrations for PI3Kα, PI3Kβ, PI3Kγ, and PI3Kδ are 0.5, 8, 20, and 2 nM, respectively. Noteworthy is the mixing of 10 μL of enzyme solution with 0.5 μLof dimethyl sulfoxide (DMSO) containing varying concentrations of the test compound. 10 μL of liver phosphatidylinositol and 2 mL of ATP solution are added to start kinase reactions. VPS34, ATP, and phosphatidylinositol have respective assay concentrations of 40 nM, 1 M, and 5 μM. |
| Cell Assay | MTT or WST-1 reagent that has already been mixed are used to measure cell proliferation. 10,000 cells are seeded in each well of 96-well plates for MTT/WST-1 assays. Cells are given DMSO or pilaralisib treatment 24 hours after plating. MTT/WST-1 assays are carried out five days after the start of treatment. |
| Animal Protocol | Mice: The animals used are male and female athymic nude mice. The weights of the mouse body and the tumor are measured after the establishment of the tumor cells as xenografts in culture. The two-tailed Student t test is used to determine statistical significance (significance is P 0.05). Pilaralisib (XL147) is prepared in either water or sterile water with 10 mmol/L of HCl and is given orally via gavage at the prescribed doses and schedules with a dose volume of 10 mL/kg. |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Orally available |
| References |
[1]. Mol Cancer Ther. 2015 Apr;14(4):931-40. [2]. Pediatr Blood Cancer. 2013 May;60(5):791-8. [3]. Proc Natl Acad Sci U S A. 2012 Feb 21;109(8):2718-23. |
| Additional Infomation |
Pilaralisib is an orally available small molecule that selectively inhibits the activity of phosphoinositide-3 kinase (PI3K). Pilaralisib has been used in trials studying the treatment of Cancer, Lymphoma, Solid Tumors, Glioblastoma, and Breast Cancer, among others. Pilaralisib is an orally bioavailable small molecule, targeting the class I phosphatidylinositol 3 kinase (PI3K) family of lipid kinases, with potential antineoplastic activity. Pilaralisib 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. Dysregulated PI3K signaling may contribute to tumor resistance to a variety of antineoplastic agents including genotoxic agents and receptor tyrosine kinase inhibitors. Mechanism of Action Pilaralisib is an orally available small molecule that selectively inhibits the activity of phosphoinositide-3 kinase (PI3K). Activation of PI3K is a frequent event in human tumors, promoting tumor cell growth, survival, and resistance to chemotherapy and radiotherapy. Inactivation of PI3K has been shown to inhibit growth and induce apoptosis (programmed cell death) in tumor cells. Pharmacodynamics In preclinical studies, Pilaralisib slowed tumor growth or caused tumor shrinkage in multiple preclinical cancer models, including breast, lung, ovarian, and prostate cancers, and gliomas. Pilaralisib has also been shown to enhance the anti- tumor effects of several chemotherapeutic agents and an inhibitor of epidermal growth factor receptor (EGFR) in preclinical cancer models. |
Solubility Data
| Solubility (In Vitro) |
DMSO: ~100 mg/mL warming (184.8 mM) Water: <1 mg/mL Ethanol: <1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (4.62 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 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 (4.62 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension 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. Solubility in Formulation 3: 10 mM HCl in sterile water: 0.5mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 1.8484 mL | 9.2418 mL | 18.4836 mL | |
| 5 mM | 0.3697 mL | 1.8484 mL | 3.6967 mL | |
| 10 mM | 0.1848 mL | 0.9242 mL | 1.8484 mL |