p70S6K (IC50 = 4 nM)

LY2584702 抑制 HCT116 结肠癌细胞中 S6 核糖体蛋白 (pS6) 的磷酸化，IC50 为 0.1-0.24 μM。 [1] LY2584702与mTOR抑制剂依维莫司或EGFR抑制剂厄洛替尼联合使用时，表现出显着的协同效应。 [2]

在 U87MG 胶质母细胞瘤和 HCT116 结肠癌异种移植模型中，LY2584702（12.5 mg/kg BID）均表现出显着的抗肿瘤功效。 [1]

RPS6KB1是核糖体蛋白S6的激酶，其分子量为70kDa，是蛋白质翻译所必需的。尽管RPS6KB1的异常激活已在多种疾病中发现，但其在非小细胞肺癌癌症中的作用和临床意义尚未得到充分研究。在这项研究中，我们发现RPS6KB1在非小细胞肺癌中过磷酸化（p-RPM6KB1），这是一个独立的不良预后标志物。尽管免疫组织化学染色（IHC）显示，非小细胞肺癌标本中总RPS6KB1和p-RPS6KB2的表达频繁，但只有p-RPS6KB1与非小细胞癌受试者的临床病理特征相关。Kaplan-Meier生存分析显示，p-RPS6KB1表达的增加表明非小细胞肺癌患者的5年总生存率（OS）较低，而RPM6KB1阳性或阴性组之间的差异并不显著。然后使用单变量和多变量Cox回归分析来确认p-RPS6KB1的独立预后价值。为了说明非小细胞肺癌中RPS6KB1磷酸化的潜在机制，我们使用LY2584702来抑制肺腺癌细胞系A549和鳞状细胞癌细胞系SK-MES-1中RPS6KB1的磷酸化。正如预期的那样，RPS6KB1去磷酸化在CCK-8试验中显著抑制了细胞增殖，并通过细胞周期分析促进了更多细胞停滞在G0-G1期。此外，RPS6KB1去磷酸化的凋亡A549细胞急剧增加，SK-MES-1呈上升趋势，表明RPS6KBl磷酸化可能参与诱导凋亡。总之，我们的数据表明，在非小细胞肺癌中，RPS6KB1与p-RPM6KB1一样被过度激活，而不仅仅是总蛋白的过度表达。RPS6KB1的磷酸化水平可作为NSCLC患者的一种新的预后标志[4]。

LY-2584702完全溶解在20 mL 10% DMSO中并储存在-80°C。在体外进行实验时，LY-2584702在0.5% Tween 80、5%丙二醇和30% PEG400中进一步稀释，以达到0.1 μM、0.2 μM、0.6 μM和1.0 μM的各种DMSO浓度。使用细胞计数试剂盒-8 (CCK-8) 评估体外细胞增殖。将已暴露于不同浓度的 LY-2584702 24 小时的 A549 和 SK-MES-1 细胞系以每孔 5 103 个细胞的密度接种在 96 孔板中，重复六次。 LY-2584702 浓度为零时用作阴性对照，或用 DMSO 处理。接种后每 24 小时测量细胞在 450 nm 处的吸光度，以测定其增殖活性。

Mice; LY-2584702 is prepared in 0.25% Tween-80 and 0.05% antifoam, and administered orally to mice (12.5 mg/kg twice daily). Injections of EOMA cells (0.3×106) are made subcutaneously into nu/nu female mice aged 6 to 8 weeks (2 sites/mouse, 4-5 mice/group). Every day, the tumor's size is determined. Animals are either given a vehicle control or the drug LY-2584702 (12.5 mg/kg twice daily, oral dosing) for treatment when tumors grow to a size of 0.01 cm3. Every 3–4 days, tumor size is determined.[3]

[1]. Eur J Cancer. 2014 Mar;50(5):867-75.

[2]. Eur J Cancer. 2014 Mar;50(5):876-84.

[3]. Cancer Res. 2015 Jan 1;75(1):40-50.
[4]. PLoS One. 2017 Aug 9;12(8):e0182891.

Background: LY2584702 tosylate (hereafter referred to as LY2584702) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway which regulates cell proliferation and survival. LY2584702 exhibited anti-tumour activity in preclinical analysis.[1]
Methods: Patients with advanced solid tumours were treated with LY2584702 orally on a 28-day cycle until the criteria for maximum tolerated dose (MTD) were met. Skin biopsies were collected for pharmacodynamic analysis, and levels of phospho-S6 protein were examined. The primary objective was to determine a phase II dose and schedule with secondary objectives of observing safety and tolerability. Dose escalation was based upon Common Terminology Criteria for Adverse Events Version 3.0.[1]
Results: Thirty-four patients were enrolled onto this phase I study and treated with LY2584702 on a QD (once-daily) or BID (twice-daily) dosing schedule. Part A dose escalation (n=22) began with 300 mg BID (n=2). Due to toxicity, this was scaled back to doses of 25mg (n=3), 50 mg (n=8), 100mg (n=3), and 200 mg (n=6) QD. Part B dose escalation (n=12) included 50 mg (n=3), 75 mg (n=3), and 100 mg (n=6) BID. Seven patients experienced dose-limiting toxicity (DLT). All DLTs were Grade 3 and included vomiting, increased lipase, nausea, hypophosphataemia, fatigue and pancreatitis.[1]
Conclusion: The MTD was determined to be 75 mg BID or 100mg QD. No responses were observed at these levels. Pharmacokinetic analysis revealed substantial variability in exposure and determined that LY2584702 treatment was not dose proportional with increasing dose. Trial registration: ClinicalTrials.gov NCT01394003.[1]

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Background: LY2584702 tosylate (hereafter referred to as LY2584702) is an oral, selective ATP competitive inhibitor of p70 S6 kinase. Preclinical studies with LY2584702 demonstrated significant synergistic activity with erlotinib and everolimus. The primary objective was to determine a phase II dose and schedule. Secondary objectives included evaluation of safety, toxicity and pharmacokinetics of LY2584702 in combination with erlotinib or everolimus.[2]
Methods: Patients with advanced solid tumours were treated with a total daily dose of 50-200mg of LY2584702 in combination with erlotinib 150 mg once daily (Arm A) or everolimus 10mg once daily (Arm B). Dose escalation was based on 3+3 design and used the Common Terminology Criteria for Adverse Events Version 4.0.[2]
Results: Twenty-nine patients were enrolled, 17 in Arm A and 12 in Arm B. Dose limiting toxicities (DLTs) in cycle 1 were observed in Arm A in four patients and consisted of Grade 3 vomiting, hypophosphataemia, pulmonary embolism and decreased clotting factor V. No DLTs were observed in Arm B at cycle 1, and the most frequent treatment-emergent adverse events related to study drug were: fatigue, anorexia, diarrhoea, nausea and vomiting. Seven patients received ≥4 cycles (3 in A, 4 in B). Best overall response was stable disease. Exposure accumulation of LY2584702 occurred with BID (twice daily) dosing. Exposure of erlotinib increased when administered in combination with LY2584702.[2]
Conclusion: LY2584702 was not well tolerated when administered with erlotinib, therefore this combination is not feasible. The combination with everolimus was better tolerated but yielded very limited clinical benefit.[2]
Trial registration: ClinicalTrials.gov NCT01115803.[2]

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Vascular tumors are endothelial cell neoplasms whose mechanisms of tumorigenesis are poorly understood. Moreover, current therapies, particularly those for malignant lesions, have little beneficial effect on clinical outcomes. In this study, we show that endothelial activation of the Akt1 kinase is sufficient to drive de novo tumor formation. Mechanistic investigations uncovered opposing functions for different Akt isoforms in this regulation, where Akt1 promotes and Akt3 inhibits vascular tumor growth. Akt3 exerted negative effects on tumor endothelial cell growth and migration by inhibiting activation of the translation regulatory kinase S6-Kinase (S6K) through modulation of Rictor expression. S6K in turn acted through a negative feedback loop to restrain Akt3 expression. Conversely, S6K signaling was increased in vascular tumor cells where Akt3 was silenced, and the growth of these tumor cells was inhibited by a novel S6K inhibitor. Overall, our findings offer a preclinical proof of concept for the therapeutic utility of treating vascular tumors, such as angiosarcomas, with S6K inhibitors.[3]

C28H27F4N7O3S

617.62

617.183

C, 54.45; H, 4.41; F, 12.30; N, 15.88; O, 7.77; S, 5.19

1082949-68-5

LY-2584702 free base;1082949-67-4;LY-2584702 hydrochloride;1082948-81-9

46205871

White to off-white solid powder

6.682

138.27

S(C1C([H])=C([H])C(C([H])([H])[H])=C([H])C=1[H])(=O)(=O)O[H].FC1C([H])=C([H])C(=C([H])C=1C(F)(F)F)C1=C([H])N(C([H])([H])[H])C(C2([H])C([H])([H])C([H])([H])N(C3C4C([H])=NN([H])C=4N=C([H])N=3)C([H])([H])C2([H])[H])=N1

HDYUXDNMHBQKAU-UHFFFAOYSA-N

InChI=1S/C21H19F4N7.C7H8O3S/c1-31-10-17(13-2-3-16(22)15(8-13)21(23,24)25)29-19(31)12-4-6-32(7-5-12)20-14-9-28-30-18(14)26-11-27-20;1-6-2-4-7(5-3-6)11(8,9)10/h2-3,8-12H,4-7H2,1H3,(H,26,27,28,30);2-5H,1H3,(H,8,9,10)

4-[4-[4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methylimidazol-2-yl]piperidin-1-yl]-1H-pyrazolo[3,4-d]pyrimidine;4-methylbenzenesulfonic acid

LYS6K2 tosylate; LY2584702; LY 2584702; LY-2584702; LYS-6K2; LYS 6K2; LY2584702 tosylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO: ~7 mg/mL (~11.3 mM)
Water: <1 mg/mL
Ethanol: <1 mg/mL

配方 1 中的溶解度: ≥ 1 mg/mL (1.62 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 10.0 mg/mL澄清DMSO储备液加入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: 1 mg/mL (1.62 mM) 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), 悬浊液; 超声助溶。
例如，若需制备1 mL的工作液，可将 100 μL 10.0 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: ≥ 1 mg/mL (1.62 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 10.0 mg/mL 澄清 DMSO 储备液加入900 μL 玉米油中，混合均匀。

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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。