LY2584702 (tosylate) is a potent, highly selective adenosine triphosphate (ATP) competitive inhibitor against p70 S6 kinase, a downstream component of the phosphatidylinositol-3-kinase signalling pathway with an IC50 value of 0.004μM. LY2584702 exhibited anti-tumour activity and was initially developed for the treatment of solid tumors[1][2].
In vitro, lung adenocarcinoma cell line A549 and squamous cell carcinoma cell line SK-MES-1 treated by LY2584702 for 24h at 0.1μM and 0.6μM, respectively significantly inhibited cell proliferation. LY2584702 treatment (0.2μM) on A549 for 72h cause more cells arrested in G0-G1 phase and cells in S or G2-M phase decreased correspondingly. In addition, LY2584702 induced more apoptotic A549 cell by Annexin V-APC/7-AAD apoptosis detection[3]. LY2584702 (1, 5, and 10μM) treated LIN28Bhi colorectal cancer cells for 48h reduced p-RPS6 levels in cells without inducing cytotoxicity. 5μM LY2584702 reduced cell migration in LIN28Bhi cells at 48 or 72 hours, respectively, when compared with the vehicle-treated control group[4]. The genetic specific variants of PPP2R5D gene are associated with neurodevelopmental disorders characterized by intellectual disability, hypotonia, seizures, macrocephaly, autism spectrum disorder, and delayed motor skill development. HEK293 cell lines treated with LY2584702 (20nM for 3h) inhibited the hyperphosphorylation of p70S6K and RPS6 in PPP2R5D variant cells. LY2584702 could be a promising therapeutic strategy for managing neurodevelopmental disorders associated with PPP2R5D mutations[5].
In vivo, LY2584702 demonstrated significant single-agent efficacy in both U87MG glioblastoma and HCT116 colon carcinoma xenograft models at two dose levels of 2.5mg/kg twice daily (BID) and 12.5mg/kg BID. LY2584702 demonstrated statistically significant tumour growth reduction at TMED50 (threshold minimum effective dose 50%) (2.3mg/kg) and TMED90 (10mg/kg) in the HCT116 colon carcinoma xenograft model[2]. 8-week old C57BL/6N male mice were challenged with a 60% High-fat diet (HFD) and orally treated with LY during 12 weeks. High-fat diet fed mice receiving LY2584702 (HFD + LY2584702) gained significantly less body weight and accumulated lower amounts of s.c. adipose tissue (SAT) and visceral adipose tissue (VAT) than their counterparts receiving only the HFD. Genes related to the lipid biosynthesis (e.g., Cyp2e1, Fasn, Elovl6) were less expressed in SAT and VAT of HFD + LY2584702 mice[6]. Mouse hemangioendothelioma endothelial EOMA cells (0.3×106) are injected subcutaneously in 6- to 8-week-old nu/nu female mice and LY2584702 was administered orally to mice (12.5mg/kg twice daily). LY2584702 treatment alone did not significantly affect the growth of pLKO tumors. However, it significantly reduced the growth of tumors with shAkt3. Inhibition of S6K activity with LY2584702 was more effective in reducing the growth of vascular tumors with loss of Akt3 than tumors with normal levels of Akt3[7].
References:
[1] Hollebecque A, Houédé N, Cohen E E W, et al. A phase Ib trial of LY2584702 tosylate, a p70 S6 inhibitor, in combination with erlotinib or everolimus in patients with solid tumours. Eur J Cancer. 2014 Mar;50(5):876-84.
[2] Tolcher A, Goldman J, Patnaik A, et al. A phase I trial of LY2584702 tosylate, a p70 S6 kinase inhibitor, in patients with advanced solid tumors. Eur J Cancer. 2014 Mar;50(5):867-75
[3] Chen B, Yang L, Zhang R, et al. Hyperphosphorylation of RPS6KB1, rather than overexpression, predicts worse prognosis in non-small cell lung cancer patients. PLoS One. 2017 Aug 9;12(8):e0182891.
[4] Shin A E, Sugiura K, Kariuki S W, et al. LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models. J Clin Invest. 2025 Jan 14;135(8):e186035.
[5] Kali A Smolen K A, Papke C M, Swingle M R, et al. Quantitative proteomics and phosphoproteomics of PP2A-PPP2R5D variants reveal deregulation of RPS6 phosphorylation via converging signaling cascades. J Biol Chem. 2023 Sep;299(9):105154.
[6] Lluch A, Veiga S R, Latorre J, et al. A compound directed against S6K1 hampers fat mass expansion and mitigates diet-induced hepatosteatosis. JCI Insight. 2022 Jul 22;7(14):e150461.
[7] Phung T L, Du W, Xue Q, et al. Akt1 and akt3 exert opposing roles in the regulation of vascular tumor growth. Cancer Res. 2015 Jan 1;75(1):40-50.
LY2584702 (tosylate) 是一种强效、高选择性的p70 S6激酶的ATP竞争性抑制剂，属于磷脂酰肌醇-3-激酶信号通路的下游组分，IC50值为0.004μM。该药物最初用于治疗实体瘤，展现出抗肿瘤活性[1][2]。
在体外实验中，肺腺癌细胞系A549和鳞状细胞癌细胞系SK-MES-1分别用0.1μM和0.6μM的LY2584702处理24小时，显著抑制了细胞增殖。A549细胞用0.2μM的LY2584702处理72小时后，更多细胞停留在G0-G1期，而S期或G2-M期的细胞相应减少。此外，通过Annexin V-APC/7-AAD凋亡检测发现，LY2584702诱导了更多的A549细胞凋亡[3]。在LIN28B高表达的结直肠癌细胞中，用1、5和10μM的LY2584702处理48小时，降低了细胞中的p-RPS6水平，且未引起细胞毒性。在划痕实验中，与对照组相比，5μM的LY2584702在48或72小时后显著减少了LIN28B高表达细胞的迁移能力[4]。在HEK293细胞系中，用20nM的LY2584702处理3小时，抑制了PPP2R5D变异细胞中p70S6K和RPS6的过度磷酸化，LY2584702可能是管理PPP2R5D相关神经发育障碍的有前景的治疗策略[5]。
在体内实验中，LY2584702在U87MG胶质母细胞瘤和HCT116结肠癌异种移植模型中，以2.5mg/kg每日两次（BID）和12.5mg/kg BID的剂量水平，显示出显著的单药疗效。在HCT116结肠癌异种移植模型中，LY2584702在TMED50（50%最小有效剂量）2.3mg/kg和TMED90（10mg/kg）时，显著减少了肿瘤生长[2]。8周龄的C57BL/6N雄性小鼠接受60%高脂饮食（HFD）挑战，并在12周内口服LY2584702。与仅接受高脂饮食的小鼠相比，接受LY2584702治疗的小鼠体重增加显著减少，皮下脂肪组织（SAT）和内脏脂肪组织（VAT）积累量也较低。与脂质生物合成相关的基因（如Cyp2e1、Fasn、Elovl6）在SAT和VAT中的表达降低[6]。将0.3×10^6的鼠血管内皮瘤内皮EOMA细胞皮下注射到6至8周龄的nu/nu雌性小鼠中，并给小鼠口服LY2584702（12.5mg/kg每日两次）。LY2584702单独治疗对pLKO肿瘤的生长没有显著影响，但它显著减少了带有shAkt3的肿瘤的生长。用LY2584702抑制S6K活性在减少Akt3缺失的血管肿瘤生长方面比正常Akt3水平的肿瘤更有效[7]。