Copanlisib HCl (formerly BAY-806946; BAY 80-6946; Aliqopa), the hydrochloride salt of Copanlisib, is a pan-class I PI3K (phosphoinositide 3-kinase) inhibitor approved in 2017 for the treatment of relapsed follicular lymphoma. It inhibits PI3Kα/β/γ/δ with IC50s of 0.5, 3.7, 6.4, and 0.7 nM in cell-free assays, respectively. In 2017, copanlisib was approved by FDA to treat adults with relapsed follicular lymphoma. BAY 80-6946 is a phosphoinositide 3-kinase (PI3K) inhibitor with potential antineoplastic activity, which inhibits proliferation with IC50 of 147 nM in HuCCT-1 (KRASG12D ) and 137 nM in EGI-1 (KRASG12D ) cell lines. BAY 80-6946 is generally well tolerated through the maximum tolerated dose (MTD) of 0.8 mg/kg. pharmacokinetics (PK) results support dosing weekly. Grade 2 or 3 hyperglycemia in the first 24 hrs after receiving a MTD dose. Pharmacokinetics, clinical SD as well as FDG-PET data are consistent with effective exposure and PI3K pathway inhibition.
理化性质和储存条件
| Molecular Weight (MW) | 553.45 |
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| Formula | C23H30Cl2N8O4 |
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| CAS No. | 1032568-63-0 (free base); 1402152-13-9 (HCl) |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 10 mM |
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| Water:<1 mg/mL |
| Ethanol: <1 mg/mL |
| Solubility (In vivo) | 10% Trifluoroacetic acid water solution: 1mg/mL |
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| Chemical Name | 2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl]pyrimidine-5-carboxamide dihydrochloride |
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| Synonyms | BAY 80-6946 2HCl; BAY806946 dihydrochloride; BAY80-6946; BAY-80-6946; BAY-806946; BAY 806946 dihydrochloride
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实验参考方法
| In Vitro | In vitro: In both KPL4 cells and LPA-stimulated PC3 cells, BAY 80-6946 reduces pAKT levels. In a subset of human cancer cell lines with PIK3CA mutations and/or overexpression of HER2, BAY 80-6946 shows antiproliferative activity and induces apoptosis. The combination of HER2-targeted therapies and BAY 80-6946 inhibits growth more effectively than either therapy used alone, and can restore sensitivity to trastuzumab and lapatinib in cells.
Kinase Assay: The effect of BAY 80-6946 on PI3Kα, PI3Kβ, and PI3Kγ activity is measured by the inhibition of 33P incorporation into phosphatidylinositol (PI) in 384-well MaxiSorp(R) plates coated with 2 μg/well of PI and phosphatidylserine (PS) (1:1 molar ratio). In each PI3K isoform assay, 9 μL of reaction buffer (50 mM MOPSO, pH 7.0, 100 mM NaCl, 4 mM MgCl2, 0.1% BSA) containing 7.5 ng of His-tagged N-terminal truncated p110α or p110β protein, or 25 ng of purified human p110γ protein, is used. The reaction is started by adding 5 μL of a 40-μM ATP solution containing 20 μCi/mL [33>/sup>P]-ATP. After 2 hours incubation at room temperature, the reaction is terminated by addition of 5 μL of a 25-mM EDTA solution. The plates are washed and Ultima Gold(TM) scintillation cocktail (25 μL) is then added. The radioactivity incorporated into the immobilized PI substrate is determined with a BetaPlate Liquid Scintillation Counter.
Cell Assay: Cell proliferation over a 72-hour period is determined using the CellTiter-Glo(R) luminescent cell viability kit. Briefly, cells are plated in separate microtiter plates. Following an overnight incubation at 37oC, luminescence values in the t=0 hour plates are determined. Test compounds diluted in growth medium are added to the t=72 hour plates, and the cells are then incubated for 72 hours at 37oC. Luminescence values are determined with a Wallac 1420 Victor2(TM) 1420 multilabel HTS counter after a 10-minute reaction with CellTiter-Glo(R) solution. The percentage inhibition of cell growth is calculated by subtracting the luminescence values in the t=0 hour plates from the corresponding values in the t=72 hour plates. Differences in values between drug-treated cells and controls are used to determine the percentage inhibition of cell growth. |
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| In Vivo | In rat KPL4 or HCT116 tumor xenograft model, BAY 80-6946 (6 mg/kg, i.v.) induces 100% complete tumor regression. In nude mice with Lu7860 erlotinib-resistant, patient-derived NSCLC and MAXF1398 patient-derived luminal breast tumor models, BAY 80-6946 (14 mg/kg, i.v.) also causes tumor growth inhibition. |
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| Animal model | Rats bearing KPL4 or HCT116 xenografts |
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| Formulation & Dosage | Formulated in PEG400/acidified water (0.1 N HCl, pH 3.5; 20/80, v/v) or 5% mannitol; 6 mg/kg; i.v. |
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| References | Mol Cancer Ther. 2013 Nov;12(11):2319-30; Breast Cancer Res Treat. 2015 Jan;149(2):373-83. |
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