A66
(Synonyms: A 66; A-66) 目录号 : GC17550
A66是一种高度特异性和选择性的p110α 抑制剂，其 IC50值为32nM。
Cas No.:1166227-08-2
Sample solution is provided at 25 µL, 10mM.
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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]。
| Cell experiment [1]: | |
Cell lines | Human rhabdomyosarcoma Rh30 cell line |
Preparation Method | Human rhabdomyosarcoma Rh30 cells were maintained in RPMI-1640 medium supplemented with 10% fetal bovine serum. Myristoylated tag was ligated in tandem with each p110 gene sequences and then inserted into pBabe-Puro plasmid. The resulting constructs were co-transfected with pGP and pE-Ampho plasmids into 293FT cells to obtain retrovirus, which were then used to infect Rh30 cells. After selection with 1μg/mL puromycin for 1 week, cells stably expressing myristoylated PI3K isoforms were pooled for validation and named as Rh30-Myr-p110. Rh30-Myr-p110 cells grown to 50% confluence in 12-well plates continued to be incubated in serum-free medium for 12h and were then exposed to A66 at 100nM for 1h. |
Reaction Conditions | 100nM; 1h |
Applications | A66 significantly inhibited the phosphorylation of Akt in human rhabdomyosarcoma Rh30-Myr-p110 cells. |
| Animal experiment [2]: | |
Animal models | Male CD1 mice |
Preparation Method | For glucose tolerance tests and pyruvate tolerance tests the mice were starved overnight and for the insulin tolerance test food was withdrawn 2h prior to the start of the experiments. A66 was dosed intraperitoneally 1h after the end of the dark cycle and 1h prior to the intraperitoneal dosing with glucose or pyruvate (2g/kg) or insulin (0.75unit/kg). |
Dosage form | 10mg/kg; 24h; i.p. |
Applications | A66 induced significant impairments in the insulin tolerance test and glucose tolerance test, and an increase in glucose production during a pyruvate tolerance test in mice. |
References: | |
| Cas No. | 1166227-08-2 | SDF | |
| 别名 | A 66; A-66 | ||
| 化学名 | (2S)-1-N-[5-(2-tert-butyl-1,3-thiazol-4-yl)-4-methyl-1,3-thiazol-2-yl]pyrrolidine-1,2-dicarboxamide | ||
| Canonical SMILES | CC1=C(SC(=N1)NC(=O)N2CCCC2C(=O)N)C3=CSC(=N3)C(C)(C)C | ||
| 分子式 | C17H23N5O2S2 | 分子量 | 393.53 |
| 溶解度 | ≥ 19.7mg/mL in DMSO | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.5411 mL | 12.7055 mL | 25.411 mL |
| 5 mM | 0.5082 mL | 2.5411 mL | 5.0822 mL |
| 10 mM | 0.2541 mL | 1.2706 mL | 2.5411 mL |
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| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
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| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
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2.
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Quality Control & SDS
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- Purity: >98.00%
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