A66

Cas：1166227-08-2

Product Information：

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 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

Synonym:

A66

A-66

A 66

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

Technical Data：

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

In Vitro：

A66 is a potent inhibitor of the wild-type and oncogenic forms of p110α but not other class-I PI3K isoforms. The p110α-specific inhibitor A66 (0.7 μM) induces a 75-80% reduction in focus formation by the highly transforming iSH2 mutants KS459delN, DKRMNS560del, and K379E. The p110α-specific inhibitor A66 reduced phosphorylation of Akt on T308 by all p85 mutants.

In Vivo：

The optimal dosing strategy for xenograft studies is determined 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 is reached 30 min after dosing ensured that the AUC0-inf (area under the curve from zero time to infinity) (6809 nM•h) is similar to that of BEZ-235 (7333 nM•h), which has a longer half-life of 2.73 h. Furthermore, the A66 on SK-OV-3 tumour tissue is tested 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. These studies show that A66 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. Levels of A66 in plasma are 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 in the tumor are 22.7±2.1 μM and 16.0±1.3 μM at the same time points.

References：

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.

Products are for research use only. Not for human use.