1166227-08-2

A-66 is a potent, selective inhibitor of the PI3K isoform p110α (IC₅₀ = 32 nM in a cell-free assay). It displays over 100-fold selectivity for p110α over other isoforms. A-66 is effective in vivo, suppressing the growth of SK-OV-3 tumor xenografts in mice. It also impairs all measures of in vivo insulin action in mice. A-66 partially suppresses B cell receptor-dependent Akt activation and proliferation.

A66 is a potent and specific p110α inhibitor. Inhibition of p110α can block phosphoinositide 3-kinase (PI3K) signalling and tumor growth in certain cell types.

ChEBI: (2S)-N1-[5-(2-tert-butyl-4-thiazolyl)-4-methyl-2-thiazolyl]pyrrolidine-1,2-dicarboxamide is a proline derivative.

This potent and highly selective p110α inhibitor (FW = 393.53; CAS 1166227-08-2; Solubility: 79 mg/mL DMSO, 1 mg/mL H2O), also known as (2S) -N1- (5- (2-tert-butylthiazol-4-yl) -4-methylthiazol-2-yl) pyrrolidine-1, 2-dicarboxamide, has a IC50 value of 32 nM for the wild-type phosphoinositide-3 kinase p110 α as well as oncogenic forms of p110α such as p110α E545K (IC50 = 43 nM) and p110α H1047R (IC50 = 43 nM) . A66 inhibition also demonstrated that cancer-specific mutations in the iSH2 (inter-SH2) and nSH2 (N-terminal SH2) domains of p85α, the regulatory subunit of phosphatidylinositide 3-kinase (PI3K), show gain of function, inducing oncogenic cellular transformation, stimulating cellular proliferation, and enhancing PI3K signaling.

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[1] STEPHEN JAMIESON. A drug targeting only p110α can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types.[J]. Biochemical Journal, 2011, 438 1: 53-62. DOI: 10.1042/bj20110502
[2] GREG C SMITH. Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo.[J]. Biochemical Journal, 2012, 442 1: 161-169. DOI: 10.1042/bj20111913
[3] LOMON SO. Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function.[J]. The Journal of Biological Chemistry, 2013: 5718-5731. DOI: 10.1074/jbc.m112.379446