PF-4708671

S6K1 (IC50 = 160 nM); S6K1 (Ki = 20 nM); S6K2 (IC50 = 65 μM)

PF-4708671 在体外抑制全长 S6K1 的活性，Ki 为 20 nM，从 IGF1 刺激的 HEK293 细胞中分离的 S6K1 的 IC50 为 0.16 μM，并且仅非常轻微地（IC50 为 65 μM）抑制密切相关的S6K2亚型。 PF-4708671 抑制 RSK1（IC50 为 4.7 μM）和 RSK2（IC50 为 9.2 μM）的效力比 S6K1 低 20 倍以上。 PF4708671 抑制 MSK1 的效力比 S6K1 低四倍 (IC50 = 0.95 μM)[1]。 HCT116 细胞用 (i) 载体 (DMSO)、(ii) OSI-906 (5 μM)、(iii) PF-4708671 (10 μM) 和 (iv) OSI-906 (5 μM)+PF-4708671 处理(10 μM) 不同的时间。单独的 OSI-906（实心方块）或单独的 PF4708671（空心圆圈）对 HCT116 细胞的治疗略微抑制细胞生长。另一方面，OSI-906 和 PF-4708671 的组合在治疗 2 天后显着减少 HCT116 细胞增殖（实心圆圈）。当 SW480 细胞用 OSI-906 和 PF-4708671 的混合物处理时，结果也相似。与媒介物、单独的 OSI-906 或单独的 PF-4708671 处理的 HCT116 或 SW480 细胞相比，OSI-906+PF-4708671 处理的细胞中集落形成也显着减少[2]。

用OSI-906+PF-4708671组合治疗的小鼠中的肿瘤生长速率明显慢于单独的OSI-906(P=0.0189)或单独的PF4708671(P=0.0165)治疗的小鼠。 15 天治疗期结束时，OSI-906+PF-4708671 治疗小鼠的平均肿瘤体积比单独使用 OSI-906 (P=0.0056) 或 PF-4708671 治疗的小鼠小约 50% （P<0.001）[2]。

PF-4708671 是 p70 核糖体 S6 激酶（S6K1 亚型）的细胞渗透性抑制剂，在无细胞测定中 Ki/IC50 为 20 nM/160 nM，对 S6K1 的选择性比 S6K2 高 400 倍，且 4- 和 >20 S6K1 的选择性分别是 MSK1 和 RSK1/2 的两倍。

这些细胞包括 GEO、HT29、SW480 和 HCT116。 XTT 和克隆形成测定用于确定 OSI-906 或 OSI-906 和 PF-4708671 如何影响细胞增殖。细胞增殖试剂盒 II (XTT) 用于进行 XTT 测定。对于克隆形成测定，将细胞（1 103 个细胞/孔）接种在 6 孔板上，然后进行药物处理（OSI-906 5 M、PF-4708671 10 M）。孵育一周后，用 1% 结晶紫对细胞进行染色，计数并记录集落数量 [2]。

Mice: The following groups (five mice/group) of female athymic nude mice (Hsd:Athymic Nude-Foxn1nu) are randomly assigned. Mice are given either OSI-906 (30 mg/kg) or vehicle (25 mM tartaric acid) for 12 days prior to the injection of HT29-L and HT29-P cells. Mice are administered the following drugs orally for 14 days prior to the injection of HCT116 cells: vehicle (25 mM tartaric acid); OSI-906 alone (30 mg/kg); PF-4708671 alone (60 mg/kg); and OSI-906 (30 mg/kg)+PF-4708671 (60 mg/kg). Each day, one dose of OSI-906, one dose of PF-4708671, and one dose of Vehicle are administered. The mice are sacrificed, and the weights of the tumors were measured, twenty-four hours after the last treatment[2].

[1]. Characterization of PF-4708671, a novel and highly specific inhibitor of p70 ribosomal S6 kinase (S6K1). Biochem J. 2010 Oct 15;431(2):245-55.

[2]. Inhibition of p70S6K1 Activation by Pdcd4 Overcomes the Resistance to an IGF-1R/IR Inhibitor in Colon Carcinoma Cells. Mol Cancer Ther. 2015 Mar;14(3):799-809.

S6K1 (p70 ribosomal S6 kinase 1) is activated by insulin and growth factors via the PI3K (phosphoinositide 3-kinase) and mTOR (mammalian target of rapamycin) signalling pathways. S6K1 regulates numerous processes, such as protein synthesis, growth, proliferation and longevity, and its inhibition has been proposed as a strategy for the treatment of cancer and insulin resistance. In the present paper we describe a novel cell-permeable inhibitor of S6K1, PF-4708671, which specifically inhibits the S6K1 isoform with a Ki of 20 nM and IC50 of 160 nM. PF-4708671 prevents the S6K1-mediated phosphorylation of S6 protein in response to IGF-1 (insulin-like growth factor 1), while having no effect upon the PMA-induced phosphorylation of substrates of the highly related RSK (p90 ribosomal S6 kinase) and MSK (mitogen- and stress-activated kinase) kinases. PF-4708671 was also found to induce phosphorylation of the T-loop and hydrophobic motif of S6K1, an effect that is dependent upon mTORC1 (mTOR complex 1). PF-4708671 is the first S6K1-specific inhibitor to be reported and will be a useful tool for delineating S6K1-specific roles downstream of mTOR.[1]

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Agents targeting insulin-like growth factor 1 receptor (IGF-1R) are being actively examined in clinical trials. Although there has been some initial success of single-agent targeting IGF-1R, attempts in later studies failed because of resistance. This study aimed to understand the effects of programmed cell death 4 (Pdcd4) on the chemosensitivity of the IGF-1R inhibitor OSI-906 in colorectal cancer cells and the mechanism underlying this impact. Using OSI-906-resistant and -sensitive colorectal cancer cells, we found that the Pdcd4 level directly correlates with cell chemosensitivity to OSI-906. In addition, tumors derived from Pdcd4 knockdown cells resist the growth inhibitory effect of OSI-906 in a colorectal cancer xenograft mouse model. Moreover, Pdcd4 enhances the antiproliferative effect of OSI-906 in resistant cells through suppression of p70S6K1 activation. Knockdown of p70S6K1, but not p70S6K2, significantly increases the chemosensitivity of OSI-906 in cultured colorectal cancer cells. Furthermore, the combination of OSI-906 and PF-4708671, a p70S6K1 inhibitor, efficiently suppresses the growth of OSI-906-resistant colon tumor cells in vitro and in vivo. Taken together, activation of p70S6K1 that is inhibited by Pdcd4 is essential for resistance to the IGF-1R inhibitor in colon tumor cells, and the combinational treatment of OSI-906 and PF-4708671 results in enhanced antiproliferation effects in colorectal cancer cells in vitro and in vivo, providing a novel venue to overcome the resistance to the IGF-1R inhibitor in treating colorectal cancer.[2]

C19H21N6F3

390.40544

390.177

C, 58.45; H, 5.42; F, 14.60; N, 21.53

1255517-76-0

1255517-76-0

51371303

White to off-white solid powder

1.3±0.1 g/cm3

572.8±50.0 °C at 760 mmHg

300.2±30.1 °C

0.0±1.6 mmHg at 25°C

1.609

3.2

60.94

1

8

4

28

510

0

FC(C1=CC=C2N=C(CN3CCN(C4=NC=NC=C4CC)CC3)NC2=C1)(F)F

FBLPQCAQRNSVHB-UHFFFAOYSA-N

InChI=1S/C19H21F3N6/c1-2-13-10-23-12-24-18(13)28-7-5-27(6-8-28)11-17-25-15-4-3-14(19(20,21)22)9-16(15)26-17/h3-4,9-10,12H,2,5-8,11H2,1H3,(H,25,26)

2-((4-(5-ethylpyrimidin-4-yl)piperazin-1-yl)methyl)-5-(trifluoromethyl)-1H-benzo[d]imidazole

PF-4708671; PF4708671; PF 4708671

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: ~30 mg/mL (76.8 mM)
Water: <1 mg/mL
Ethanol: 8 mg/mL (20.5 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (6.40 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (6.40 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (6.40 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 4 中的溶解度: 30% PEG400+0.5% Tween80+5% propylene glycol: 30mg/mL

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。