A66

Intraperitoneal injection

(2S)-N1-(5-(2-tert-butylthiazol-4-yl)-4-methylthiazol-2-yl)pyrrolidine-1, 2-dicarboxamide

100 mg/kg once daily (QD) or 75 mg/kg twice daily (BID)

Formulated in 20% 2-hydroxypropyl-beta-cyclodextrin in water

In addition to the wild-type p110alpha, A66 also potently inhibits the oncogenic forms of p110alpha such as p110alpha E545K and p110alpha H1047R with IC50 of 30 nM and 43 nM, respectively. Unlike PIK-75, A66 displays >100 fold selectivity for p110alpha over other class-I PI3K isoforms. Among the class-II PI3Ks, class-III PI3K and PI4Ks, A66 only exhibits limited cross-reactivity with the class-II PI3K PI3KC2beta and the PI4Kbeta isoform of PI4K with IC50 of 462 nM and 236 nM, respectively. A66 exhibits no inhibitory activity against other lipid kinases or the related kinases DNA-PK and mTOR. A66 has a higher degree of specificity compared with PIK-75 when tested at 10 uM against two large panels of 110 protein kinases and 318 kinases. Inhibition of p110alpha alone by A66 treatment is sufficient to block insulin signalling to Akt/PKB in certain cell lines that harbor H1047R mutations in PIK3CA and have high levels of p110alpha and class-Ia PI3K activity. [1] A66 treatment at 0.7 uM induces a 75-80% reduction in focus formation by the highly transforming p85alpha iSH2 mutants KS459delN, DKRMN-S560del, and K379E, and reduces the phosphorylation of Akt on T308 by all p85 mutants. [2]

PI3K (human) HTRF Assay, The p110alpha isoform is produced in-house by co-expressing full-length human p85alpha with the indicated human full-length catalytic subunit containing a histidine tag at the N-terminus to allow purification. The p110alpha is titrated and used at a concentration between EC65-EC80 values. IC50 value is evaluated using the PI3K (human) HTRF Assay.

A66 Chemical Structure

DMSO 79 mg/mL, Water <1 mg/mL, Ethanol 1 mg/mL