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Purity: ≥98%
A66 is a novel, potent, reversible, ATP-competitive and highly selective p110α inhibitor with potential anticancer activity. It showed >100 fold selectivity for p110α over other class-I PI3K isoforms and has an IC50 for inhibiting p110α of 32 nM in a cell-free assay.
| Targets |
p110α (IC50 = 32 nM); p110α E545K (IC50 = 30 nM); p110α H1047R (IC50 = 43 nM); p110γ (IC50 = 3480 nM); PI3K-C2β (IC50 = 462 nM); PI4Kβ (IC50 = 236 nM)
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| ln Vitro |
The oncogenic forms of p110α, such as p110α E545K and p110α H1047R, are also potently inhibited by A66, with IC50 values of 30 nM and 43 nM, respectively. When compared to other class-I PI3K isoforms, A66 exhibits >100 fold selectivity for p110α, in contrast to PIK-75. Among the class-II PI3Ks, class-III PI3K and PI4Ks, A66 only exhibits limited cross-reactivity with the class-II PI3K PI3KC2β and the PI4Kβ isoform of PI4K with IC50 of 462 nM and 236 nM, respectively. The related kinases DNA-PK and mTOR as well as other lipid kinases are not inhibited by A66. When compared to PIK-75, A66 has a higher level of specificity when tested at 10 μM against two sizable panels of 110 protein kinases and 318 kinases. In some cell lines with H1047R mutations in PIK3CA and high levels of p110 and class-Ia PI3K activity, inhibition of p110α by A66 treatment is sufficient to block insulin signaling to Akt/PKB.[1] The highly transforming p85 iSH2 mutants KS459delN, DKRMN-S560del, and K379E experience a 75–80% reduction in focus formation after receiving 0.7 μM of A66, and all p85α iSH2 mutants have lessened Akt phosphorylation on T308.[2]
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| ln Vivo |
In vivo, at 1 hour and 6 hours after dosing, a single dose of A66 at 100 mg/kg results in a significant decrease in the phosphorylation of Akt/PKB and p70 S6 kinase, but not of ERK. A66 causes SK-OV-3 xenografted tumors to grow significantly more slowly than the well-known pan-PI3K inhibitor BEZ-235, with average TGI of 45.9% and 29.9%, respectively, when administered at doses of 100 mg/kg once daily (QD) for 21 days or 75 mg/kg twice daily (BID) for 16 days. While causing a non-significant reduction in tumor volume in the U87MG xenograft model, QD dosing of A66 also causes a significant reduction in tumor volume in the HCT-116 xenograft model with a TGI of 77.2%.[1] In male CD1 mice, administration of A66 at 10 mg/kg results in significant impairments in the ITT (insulin tolerance test) and GTT (glucose tolerance test), as well as an increase in glucose production during a PTT (pyruvate tolerance test) that is almost as severe as that caused by pan-PI3K inhibitors. [3]
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| Enzyme Assay |
The PI3K (human) HTRF Assay is used to calculate IC50 values. Invitrogen provides the p85α/p110δ . All other isoforms are made on-site by combining full-length human p85α with the appropriate full-length human catalytic subunit, which is marked with a histidine tag at the N-terminus to facilitate purification. The concentration at which the PI3Ks are used is titrated between their EC65 and EC80 values. Using an antibody to p85α N-SH2 (N-Src homology 2) domain, PI3K activity in immunoprecipitates is measured. The National Centre for Protein Kinase Profiling and Invitrogen Drug Discovery Services conduct assays for additional lipid kinases and protein kinases[1].
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| Animal Protocol |
Mice: Subcutaneous inoculation of 5×106 U87MG, SK-OV-3, or HCT-116 cells in PBS is performed on the right flank of age-matched, pathogen-free Rag1-/- or NIH-III mice. Based on the formula (L×w2)×π/6 (where L is the longest tumour diameter and w is the perpendicular diameter), tumour volume (mm3) is calculated using the tumor diameter as measured by electronic calipers. While BEZ-235 is administered in 10% ethanol, A66 is given in 20% 2-hydroxypropyl-β-cyclodextrin in water. The A66 dosing vehicle is given to control mice only. The drugs are administered intraperitoneally at a dose volume of 10 mL/kg of body weight as the free base equivalent. When tumors have grown to a diameter of about 8 to 9 mm, mice are given a single dose of A66 or the control substance for tumor pharmacodynamic studies. The tumors are removed, biopulverized, and the protein concentration is measured before the animals are killed 1 or 6 hours after the last dose.
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| References | |
| Additional Infomation |
(2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide is a proline derivative.
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| Molecular Formula |
C17H23N5O2S2
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|---|---|
| Molecular Weight |
393.5268
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| Exact Mass |
393.129
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| Elemental Analysis |
C, 51.89; H, 5.89; N, 17.80; O, 8.13; S, 16.29
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| CAS # |
1166227-08-2
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| Related CAS # |
1166227-08-2
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| PubChem CID |
42636535
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.4±0.1 g/cm3
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| Index of Refraction |
1.640
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| LogP |
0.63
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
556
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| Defined Atom Stereocenter Count |
1
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| SMILES |
S1C([H])=C(C2=C(C([H])([H])[H])N=C(N([H])C(N3C([H])([H])C([H])([H])C([H])([H])[C@@]3([H])C(N([H])[H])=O)=O)S2)N=C1C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H]
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| InChi Key |
HBPXWEPKNBHKAX-NSHDSACASA-N
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| InChi Code |
InChI=1S/C17H23N5O2S2/c1-9-12(10-8-25-14(20-10)17(2,3)4)26-15(19-9)21-16(24)22-7-5-6-11(22)13(18)23/h8,11H,5-7H2,1-4H3,(H2,18,23)(H,19,21,24)/t11-/m0/s1
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| Chemical Name |
(2S)-1-N-[5-(2-tert-butyl-1,3-thiazol-4-yl)-4-methyl-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide
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| Synonyms |
A-66; A66; A 66
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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: ~79 mg/mL (~200.7 mM)
Water: ~1 mg/mL (~2.5 mM) Ethanol: ~4 mg/mL (~26.8 mM) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.35 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 (6.35 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 (6.35 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: 15% Captisol: 8mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5411 mL | 12.7055 mL | 25.4110 mL | |
| 5 mM | 0.5082 mL | 2.5411 mL | 5.0822 mL | |
| 10 mM | 0.2541 mL | 1.2706 mL | 2.5411 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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