A66
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MedKoo CAT#: 407127

CAS#: 1166227-08-2

Description: A66 is a potent and highly selective p110α inhibitor with IC50 of 32 nM in a cell-free assay, >100 fold selectivity for p110α over other class-I PI3K isoforms. A66 blocks phosphoinositide 3-kinase signalling and tumour growth in certain cell types.


Chemical Structure

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A66
CAS# 1166227-08-2

Theoretical Analysis

MedKoo Cat#: 407127
Name: A66
CAS#: 1166227-08-2
Chemical Formula: C17H23N5O2S2
Exact Mass: 393.12932
Molecular Weight: 393.52
Elemental Analysis: C, 51.89; H, 5.89; N, 17.80; O, 8.13; S, 16.29

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10.0mg USD 150.0 Same Day
25.0mg USD 250.0 Same Day
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100.0mg USD 650.0 Same Day
200.0mg USD 850.0 Same Day
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1.0g USD 2250.0 2 Weeks
2.0g USD 3950.0 2 Weeks
5.0g USD 6450.0 2 Weeks
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Synonym: A66; A-66; A 66.

IUPAC/Chemical Name: (S)-N1-(2-(tert-butyl)-4'-methyl-[4,5'-bithiazol]-2'-yl)pyrrolidine-1,2-dicarboxamide

InChi Key: HBPXWEPKNBHKAX-NSHDSACASA-N

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

SMILES Code: O=C(N1[C@H](C(N)=O)CCC1)NC2=NC(C)=C(C3=CSC(C(C)(C)C)=N3)S2

Appearance: Solid powder

Purity: >98% (or refer to the Certificate of Analysis)

Shipping Condition: Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.

Storage Condition: Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).

Solubility: Soluble in DMSO, not in water

Shelf Life: >2 years if stored properly

Drug Formulation: This drug may be formulated in DMSO

Stock Solution Storage: 0 - 4 C for short term (days to weeks), or -20 C for long term (months).

HS Tariff Code: 2934.99.9001

Biological target: A66 is a highly specific and selective p110α inhibitor with an IC50 of 32 nM.
In vitro activity: It was sought to determine which PI3K isoforms contribute to adipogenesis as well as the regulation of the levels of Topo IIα using the selective inhibitors A66 (p110α), TGX-221 (p110β) and PI3065 (p110δ). Addition of A66 reduced the storage of triglycerides dosedependently reaching the same levels obtained by LY294002 addition at the highest concentration of A66 (10 μM) (Fig. 2B–C). The levels of Topo IIα were also affected by the addition of these PI3K inhibitors with most effect seen at higher doses of A66 (1 and 10 μM). Considering that Topoisomerases II are targets in cancer chemotherapy, the results highlight that treatment of cancer with Topo II inhibitors may alter metabolic processes in the adipose tissue. Reference: Vaccine. 2011 Oct 19;29(45):8002-11. https://pubmed.ncbi.nlm.nih.gov/27404349/
In vivo activity: To investigate whether the inhibitory effects of A66 S on activation of Akt/PKB signalling translated into the ability to block cell growth in vivo, xenograft studies were performed alongside the well-established pan-PI3K inhibitor BEZ-235 in U87MG cells, which are PTEN-null, and HCT-116 and SK-OV-3 cells, both of which contain H1047R mutations. First, the optimal dosing strategy was determined for xenograft studies by investigating the drug pharmacokinetics after a dose of 10 mg/kg of body weight by intraperitoneal injection in CD-1 mice. Despite a short half-life of only 0.42 h, the large Cmax (8247 nM) of A66 S that was reached 30 min after dosing ensured that the AUC0-inf (area under the curve from zero time to infinity) (6809 nM·h) was similar to that of BEZ-235 (7333 nM·h), which has a longer half-life of 2.73 h (Table 3). Furthermore, the effect of the A66 S form on SK-OV-3 tumour tissue was tested in vivo using a single dose of 100 mg/kg of body weight to determine whether a long-lasting effect of the drug could be achieved on target tissues (Figure 6). These studies show that A66 S causes a profound reduction in the phosphorylation of Akt/PKB and p70 S6 kinase, but not of ERK (extracellular-signal-regulated kinase), at both 1 and 6 h after dosing (Figure 6). This is consistent with A66 S having a full inhibitory effect on PI3K signalling in the tumours during this time. In the present study, levels of A66 S in plasma were determined to be 21.1±1.2 μM and 9.1±1.1 μM at 1 and 6 h after drug injection, whereas levels of A66 S in the tumour were 22.7±2.1 μM and 16.0±1.3 μM at the same time points. Thus, the retention of drug in the tumour is likely to explain the persistence of the inhibitory effect. Reference: Biochem J. 2011 Aug 15; 438(Pt 1): 53–62. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3174055/

Solubility Data

Solvent Max Conc. mg/mL Max Conc. mM
Solubility
DMSO 44.5 113.08

Preparing Stock Solutions

The following data is based on the product molecular weight 393.52 Batch specific molecular weights may vary from batch to batch due to the degree of hydration, which will affect the solvent volumes required to prepare stock solutions.

Recalculate based on batch purity %
Concentration / Solvent Volume / Mass 1 mg 5 mg 10 mg
1 mM 1.15 mL 5.76 mL 11.51 mL
5 mM 0.23 mL 1.15 mL 2.3 mL
10 mM 0.12 mL 0.58 mL 1.15 mL
50 mM 0.02 mL 0.12 mL 0.23 mL
Formulation protocol: 1. Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011 Aug 15;438(1):53-62. doi: 10.1042/BJ20110502. PMID: 21668414; PMCID: PMC3174055. 2. Jacobsen RG, Mazloumi Gavgani F, Mellgren G, Lewis AE. DNA Topoisomerase IIα contributes to the early steps of adipogenesis in 3T3-L1 cells. Cell Signal. 2016 Oct;28(10):1593-603. doi: 10.1016/j.cellsig.2016.07.002. Epub 2016 Jul 9. PMID: 27404349. 3. Seyoum B, Yano M, Pirofski LA. The innate immune response to Streptococcus pneumoniae in the lung depends on serotype and host response. Vaccine. 2011 Oct 19;29(45):8002-11. doi: 10.1016/j.vaccine.2011.08.064. Epub 2011 Aug 22. PMID: 21864623; PMCID: PMC3191269.
In vitro protocol: 1. Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011 Aug 15;438(1):53-62. doi: 10.1042/BJ20110502. PMID: 21668414; PMCID: PMC3174055. 2. Jacobsen RG, Mazloumi Gavgani F, Mellgren G, Lewis AE. DNA Topoisomerase IIα contributes to the early steps of adipogenesis in 3T3-L1 cells. Cell Signal. 2016 Oct;28(10):1593-603. doi: 10.1016/j.cellsig.2016.07.002. Epub 2016 Jul 9. PMID: 27404349.
In vivo protocol: 1. Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011 Aug 15;438(1):53-62. doi: 10.1042/BJ20110502. PMID: 21668414; PMCID: PMC3174055. 2. Seyoum B, Yano M, Pirofski LA. The innate immune response to Streptococcus pneumoniae in the lung depends on serotype and host response. Vaccine. 2011 Oct 19;29(45):8002-11. doi: 10.1016/j.vaccine.2011.08.064. Epub 2011 Aug 22. PMID: 21864623; PMCID: PMC3191269.

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1: Sweetlove M, Wrightson E, Kolekar S, Rewcastle GW, Baguley BC, Shepherd PR, Jamieson SM. Inhibitors of pan-PI3K Signaling Synergize with BRAF or MEK Inhibitors to Prevent BRAF-Mutant Melanoma Cell Growth. Front Oncol. 2015 Jun 16;5:135. doi: 10.3389/fonc.2015.00135. eCollection 2015. PubMed PMID: 26137449; PubMed Central PMCID: PMC4468830.

2: Ni Y, Sinnett-Smith J, Young SH, Rozengurt E. PKD1 mediates negative feedback of PI3K/Akt activation in response to G protein-coupled receptors. PLoS One. 2013 Sep 9;8(9):e73149. doi: 10.1371/journal.pone.0073149. eCollection 2013. Erratum in: PLoS One. 2014;9(1). doi:10.1371/annotation/70d3c7b0-9718-4bb1-abed-d0defc3b7fc4. PubMed PMID: 24039875; PubMed Central PMCID: PMC3767810.

3: Buchanan CM, Dickson JM, Lee WJ, Guthridge MA, Kendall JD, Shepherd PR. Oncogenic mutations of p110α isoform of PI 3-kinase upregulate its protein kinase activity. PLoS One. 2013 Aug 1;8(8):e71337. doi: 10.1371/journal.pone.0071337. Print 2013. PubMed PMID: 23936502; PubMed Central PMCID: PMC3731339.

4: Wang X, Li JP, Yang Y, Ding J, Meng LH. A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth. Acta Pharmacol Sin. 2013 Sep;34(9):1201-7. doi: 10.1038/aps.2013.81. Epub 2013 Jul 29. PubMed PMID: 23892273; PubMed Central PMCID: PMC4003165.

5: Smith GC, Ong WK, Costa JL, Watson M, Cornish J, Grey A, Gamble GD, Dickinson M, Leung S, Rewcastle GW, Han W, Shepherd PR. Extended treatment with selective phosphatidylinositol 3-kinase and mTOR inhibitors has effects on metabolism, growth, behaviour and bone strength. FEBS J. 2013 Nov;280(21):5337-49. doi: 10.1111/febs.12428. Epub 2013 Aug 12. PubMed PMID: 23837532.

6: Weigelt B, Warne PH, Lambros MB, Reis-Filho JS, Downward J. PI3K pathway dependencies in endometrioid endometrial cancer cell lines. Clin Cancer Res. 2013 Jul 1;19(13):3533-44. doi: 10.1158/1078-0432.CCR-12-3815. Epub 2013 May 14. PubMed PMID: 23674493; PubMed Central PMCID: PMC3700760.

7: Smith GC, Ong WK, Rewcastle GW, Kendall JD, Han W, Shepherd PR. Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo. Biochem J. 2012 Feb 15;442(1):161-9. doi: 10.1042/BJ20111913. PubMed PMID: 22142257; PubMed Central PMCID: PMC3343648.

8: Jamieson S, Flanagan JU, Kolekar S, Buchanan C, Kendall JD, Lee WJ, Rewcastle GW, Denny WA, Singh R, Dickson J, Baguley BC, Shepherd PR. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types. Biochem J. 2011 Aug 15;438(1):53-62. doi: 10.1042/BJ20110502. PubMed PMID: 21668414; PubMed Central PMCID: PMC3174055.

A66

10.0mg / USD 150.0