A66 is a highly specific and selective p110α inhibitor with an IC50 value of 32nM[1, 2]. A66 can also inhibit p110α mutation such as p110α E545K and p110α H1047R, which have the IC50 values of 30nM and 43nM[1]. A66 can inhibit tumor necrosis factor induced necroptosis[3].
A66 (100nM; 24h) markedly opposed the increased expression of Ido1 and Tgfb1 transcripts by TGF-β in mouse plasmacytoid dendritic cells[4]. A66 (100nM; 1h) reduced lipid kinase activity in MT (polyoma middle T antigen) tumor cells[5]. A66 (100nM; 1h) significantly inhibited the phosphorylation of Akt in human rhabdomyosarcoma Rh30 cells tranfected p110 retrovirus[6].
A66 (10mg/kg; i.p. ; 24h) induced an increase in glucose production during a pyruvate (2g/kg; i.p. ) tolerance test in mice[7]. A66 (10mg/kg; i.p. ; 21 day) significant delayed in growth of SK-OV-3 cells derived xenograft tumours in mice xenograft model (SK-OV-3 cells were subcutaneously inoculated on the right flank of the mice)[1].
References:
[1] JAMIESON S, FLANAGAN J U, KOLEKAR S, et al. A drug targeting only p110alpha can block phosphoinositide 3-kinase signalling and tumour growth in certain cell types [J]. Biochem J, 2011, 438(1): 53-62.
[2] SUN M, HILLMANN P, HOFMANN B T, et al. Cancer-derived mutations in the regulatory subunit p85alpha of phosphoinositide 3-kinase function through the catalytic subunit p110alpha [J]. Proc Natl Acad Sci U S A, 2010, 107(35): 15547-52.
[3] HU S, CHANG X, ZHU H, et al. PI3K mediates tumor necrosis factor induced-necroptosis through initiating RIP1-RIP3-MLKL signaling pathway activation [J]. Cytokine, 2020, 129(155046.
[4] IACONO A, POMPA A, DE MARCHIS F, et al. Class IA PI3Ks regulate subcellular and functional dynamics of IDO1 [J]. EMBO Rep, 2020, 21(12): e49756.
[5] UTERMARK T, RAO T, CHENG H, et al. The p110alpha and p110beta isoforms of PI3K play divergent roles in mammary gland development and tumorigenesis [J]. Genes Dev, 2012, 26(14): 1573-86.
[6] WANG X, LI J P, YANG Y, et al. A pharmacological model reveals biased dependency on PI3K isoforms for tumor cell growth [J]. Acta Pharmacol Sin, 2013, 34(9): 1201-7.
[7] SMITH G C, ONG W K, REWCASTLE G W, et al. Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo [J]. Biochem J, 2012, 442(1): 161-9.
A66是一种高度特异性和选择性的p110α抑制剂，其IC50值为32nM [1, 2]。A66 还可以抑制p110α的突变体，如p110α E545K和p110α H1047R，这些突变体的IC50值分别为30nM和43nM [1]。A66可以抑制肿瘤坏死因子诱导的凋亡[3]。
A66（100nM; 24h）显著抑制了TGF-β在小鼠浆细胞样树突状细胞中诱导的Ido1和Tgfb1转录本表达增加[4]。A66（100nM; 1h）减少了多瘤中间T抗原（MT）肿瘤细胞中的脂质激酶活性[5]。A66（100nM; 1h）显著抑制了转染p110逆转录病毒的人类横纹肌肉瘤Rh30细胞中Akt的磷酸化[6]。
使用A66（10mg/kg; i.p. ; 24h）处理小鼠，A66在小鼠丙酮酸（2g/kg; i.p. ）耐量试验中诱导葡萄糖生成增加[7]。使用A66（10mg/kg; i.p. ; 21 day）处理SK-OV-3细胞注射于小鼠后腹的小鼠异种移植模型，A66明显延迟SK-OV-3来源的异种移植肿瘤在小鼠体内的生长[1]。