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Purity: ≥98%
Samotolisib (LY3023414; GTPL8918) is an orally bioactive, selective and ATP competitive inhibitor of the class I PI3K isoforms, mTOR and DNA-PK with IC50s of 6.07 nM, 77.6 nM, 38 nM, 23.8 nM, 4.24 nM and 165 nM for PI3Kα, PI3Kβ, PI3Kδ, PI3Kγ, DNA-PK and mTOR, respectively. LY3023414 exhibits strong solubility over a broad pH range. LY3023414 was found to potently and selectively inhibit class I PI3K isoforms, mTORC1/2, and DNA-PK at low concentrations during in vitro biochemical testing against roughly 266 kinases. Additionally, LY3023414's inhibition of PI3K/AKT/mTOR signaling resulted in G1 cell-cycle arrest and had a significant antiproliferative effect on a panel of cancer cells.
| Targets |
PI3Kα (IC50 = 6.07 nM); PI3Kγ (IC50 = 23.8 nM); PI3Kδ (IC50 = 38 nM); PI3Kβ (IC50 = 77.6 nM); DNA-PK (IC50 = 4.24 nM); mTOR (IC50 = 165 nM); mTORC1; mTORC2
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| ln Vitro |
LY3023414 shows high solubility across a wide pH range. In vitro, LY3023414 inhibition of PI3K/AKT/mTOR signaling causes G1 cell-cycle arrest and led to a significant reduction in cancer cell proliferation. Inhibition of PI3K and mTOR by LY3023414 is examined in PTEN-deficient U87 MG glioblastoma cell line assays. With an IC50 of 106 nM, LY3023414 prevents the phosphorylation of AKT at position T308 downstream of PI3K. Similar to this, LY3023414 prevents mTORC2 from phosphorylating AKT at position S473 (IC50 = 94.2 nM), as well as p70S6K (position T389; IC50 = 10.6 nM) and 4E-BP1 (positions T37/46; IC50 = 187 nM) kinase targets of mTORC1.
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| ln Vivo |
In vivo, LY3023414 exhibits high bioavailability and dose-dependent dephosphorylation of downstream substrates of the PI3K/AKT/mTOR pathway like AKT, S6K, S6RP, and 4E-BP1 for 4 to 6 hours, which is consistent with the medication's half-life of 2 hours. For its antitumor activity, intermittent target inhibition is sufficient. In vivo target inhibition of LY3023414 is time- and dose-dependent. Phase 1 and 2 clinical trials are currently being conducted to evaluate it for the treatment of human malignancies[1].
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| Enzyme Assay |
The selectivity and inhibitory potential of LY3023414 are assessed against a panel of 192 kinases in PC-3 cell lysates using the KiNativ platform and a panel of 102 kinases as purified enzymes from Cerep. Together, the 2 kinase panels covered approximately 266 unique kinases. These kinases are tested with three concentrations of LY3023414 to measure inhibition and calculate approximate IC50 values. The IC50 of LY3023414 for PI3Kα is measured using 5 nM recombinant human PI3Kα, 0.01 mM ATP with a 1.76 mM Triton X 100/0.04 mM PIP2/0.2 mM PS mixed micelle as the lipid substrate in a scintillation proximity assay (SPA) with neomycin-linked beads. The IC50 of LY3023414 for PI3Kβ is measured using a mixed micelle SPA format with 0.04 mM ATP with a 0.27 mM Triton X 100/0.05 mM PIP2/0.04 mM PA mixed micelle as the lipid substrate. The IC50s of PI3Kδ and PI3Kγand of DNA-PK are measured. The IC50 for mTOR is measured.
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| Cell Assay |
The CellTiter-Glo luminescent cell viability assay system is used to measure the antiproliferative effects of Samotolisib after 2 cell doublings on cells plated on plastic or incubated for 2 weeks in soft agar with a collection of standard cell lines and human patient–derived tumor xenografts passaged in nude mice. RKO and SK-OV-3 cells, MOLT-4 and L-363 cells, DLD-1, HCT-116, HCT-15, and NCI-H460 cells are all used in the soft-agar assay. By using STR to genotype the cell lines, existing STR reference genotypes are used to match the results. The Affymetrix genome-wide human SNP Array 6.0 and whole-exome sequencing are used to characterize Oncotest PDX models, including model MX1, which was originally derived at NCI. The results of genetic identity analyses demonstrate that each PDX model is derived from a different patient sample. Samotolisib is combined with other therapeutic agents in predetermined concentration ratios that correspond to the IC50 equivalents of each individual agent for the purpose of conducting combination studies. It is determined how many combinations are present at 50% inhibition (CI50)[1].
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| Animal Protocol |
Mice; Xenograft tumors are implanted subcutaneously in athymic nude, CD-1 nude mice, and NMRI athymic nude mice. The E-myc transgenic orthotopic mutant PI3K E545K-driven leukemia model is based on B6.Cg-Tg(IghMyc)22Bri/J and C57BL/6NTac mice and is comparable to the Akt1 E17K cancer model. Samotolisib is prepared in 1% HEC in distilled water with 0.25% polysorbate 80 and 0.05% Dow-Corning Antifoam 1510-US, and it is given orally through a gavage (final volume: 0.2 mL) according to the recommended doses and schedules. After tumor volumes reach 150 to 200 mm3, efficacy and in vivo target inhibition studies are conducted. After giving a single dose of Samotolisib to tumor-bearing mice, target inhibition studies are carried out over a period of time. The MSD-ELISA multiplex method is used to collect, flash-freeze, lyse, and then analyze tumor samples.
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| References |
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| Molecular Formula |
C23H26N4O3
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| Molecular Weight |
406.48
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| Exact Mass |
406.2005
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| Elemental Analysis |
C, 67.96; H, 6.45; N, 13.78; O, 11.81
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| CAS # |
1386874-06-1
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| Related CAS # |
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| Appearance |
Solid powder
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| SMILES |
C[C@@H](CN1C2=C3C=C(C=CC3=NC=C2N(C1=O)C)C4=CC(=CN=C4)C(C)(C)O)OC
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| InChi Key |
ACCFLVVUVBJNGT-AWEZNQCLSA-N
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| InChi Code |
InChI=1S/C23H26N4O3/c1-14(30-5)13-27-21-18-9-15(16-8-17(11-24-10-16)23(2,3)29)6-7-19(18)25-12-20(21)26(4)22(27)28/h6-12,14,29H,13H2,1-5H3/t14-/m0/s1
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| Chemical Name |
8-[5-(2-hydroxypropan-2-yl)pyridin-3-yl]-1-[(2S)-2-methoxypropyl]-3-methylimidazo[4,5-c]quinolin-2-one
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.15 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 (6.15 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. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 5: ≥ 2.5 mg/mL (6.15 mM) (saturation unknown) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. 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 6: ≥ 0.5 mg/mL (1.23 mM) (saturation unknown) in 1% DMSO 99% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4601 mL | 12.3007 mL | 24.6015 mL | |
| 5 mM | 0.4920 mL | 2.4601 mL | 4.9203 mL | |
| 10 mM | 0.2460 mL | 1.2301 mL | 2.4601 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.
| NCT Number | Status | Interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT03155620 | Recruiting | Drug: Samotolisib Drug: Selpercatinib |
Malignant Glioma Recurrent Glioma |
National Cancer Institute (NCI) |
July 24, 2017 | Phase 2 |
| NCT03213678 | Active Recruiting |
Drug: Samotolisib Procedure: X-Ray Imaging |
Malignant Glioma Recurrent Glioma |
National Cancer Institute (NCI) |
July 31, 2017 | Phase 2 |
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