NEWS ｜ 23 August 2024

WIKIMOLE—LY294002

By TargetMol

LY294002(SF 1101) is a broad-spectrum PI3K inhibitor that inhibits PI3Kα, PI3Kδ, and PI3Kβ (IC50=0.5/0.57/0.97 μM). It is also a DNA-PK inhibitor (IC50=1.4 μM) and a CK2 inhibitor (IC50=98 nM), and it can induce apoptosis and autophagy.

Mechanism of Action

-Selective Inhibition of PI3K

LY294002(SF 1101) inhibits PI3K by directly binding to its catalytic site, preventing the conversion of PIP2 to PIP3. This inhibition reduces PIP3 levels, thereby affecting the activation of AKT and other downstream signaling molecules.

AKT (also known as Protein Kinase B) is a key downstream effector of the PI3K signaling pathway, and its activation depends on the production of PIP3. By inhibiting PI3K, LY294002 (SF 1101) reduces PIP3 levels, thereby decreasing AKT activation. This leads to the modulation of various biological processes regulated by AKT, including cell survival, proliferation, and migration.

-Impact on the mTOR Signaling Pathway

mTOR is a key molecule regulating cell growth and metabolism, and its activation is dependent on the PI3K/AKT pathway. LY294002 (SF 1101) indirectly impacts the mTOR pathway by inhibiting PI3K, which may affect cellular metabolism, proliferation, and growth.

-Non-specific inhibition of DNA-PK

?Non-specific inhibition: Although LY294002 (SF 1101) primarily targets PI3K, it also exhibits inhibitory effects on DNA-PK. This inhibition may be due to the non-specific nature of LY294002 (SF 1101), allowing it to interfere with other kinases, including DNA-PK.

?Impact on DNA repair: The inhibition of DNA-PK by LY294002 (SF 1101) can affect the DNA repair process. Since DNA-PK is a key enzyme in the DNA repair process, the inhibition by LY294002 may lead to incomplete repair of DNA double-strand breaks, thereby increasing the cell's sensitivity to DNA damage.

Application

- Cell Signaling Research

LY294002 (SF 1101) is a crucial tool for studying the PI3K/Akt signaling pathway. By inhibiting PI3K activity, LY294002 (SF 1101) allows researchers to explore the role of the PI3K/Akt pathway in cell growth, survival, metabolism, and other biological processes.

- Apoptosis Research

LY294002 (SF 1101) induces apoptosis by inhibiting the PI3K/Akt pathway. It helps researchers understand how the PI3K/Akt pathway regulates the apoptosis process by affecting pro-apoptotic signals, cell cycle arrest, and anti-apoptotic signals. In cancer research, LY294002 (SF 1101) can also be used as part of drug screening to evaluate the impact of PI3K pathway inhibition on cancer cell apoptosis, aiding in the discovery of potential anticancer therapeutic strategies.

- Autophagy Research

In various disease models, such as neurodegenerative diseases and metabolic disorders, LY294002 (SF 1101) helps uncover the potential role of autophagy in disease progression and treatment by modulating autophagy levels.

References

[1] Zhao J, Yan Y, Zhen S, Yu L, Ding J, Tang Q, Liu L, Zhu H, Xie M. LY294002 alleviates bone cancer pain by reducing mitochondrial dysfunction and the inflammatory response. Int J Mol Med. 2023 May;51(5):42.

[2] Hou Y, Wang K, Wan W, Cheng Y, Pu X, Ye X. Resveratrol provides neuroprotection by regulating the JAK2/STAT3/PI3K/AKT/mTOR pathway after stroke in rats. Genes Dis. 2018 Jun 15;5(3):245-255.

[3] Hu X, Xu Q, Wan H, Hu Y, Xing S, Yang H, Gao Y, He Z. PI3K-Akt-mTOR/PFKFB3 pathway mediated lung fibroblast aerobic glycolysis and collagen synthesis in lipopolysaccharide-induced pulmonary fibrosis. Lab Invest. 2020 Jun;100(6):801-811.

[4] Lin Y, Zhu X, Li Y, Dou Y, Wang J, Qi R, Ma L. LY294002 ameliorates psoriatic skin inflammation in mice via blocking the Notch1/Hes1-PTEN/AKT/IL-17A feedback loop. Clin Exp Immunol. 2023 Jul 5;213(1):114-124.

[5] He K, Yu X, Wang X, Tang L, Cao Y, Xia J, Cheng J. Baicalein and Ly294002 induces liver cancer cells apoptosis via regulating phosphatidyl inositol 3-kinase/Akt signaling pathway. J Cancer Res Ther. 2018 Jun;14(Supplement):S519-S525.

[6] Gong C, Liao H, Wang J, Lin Y, Qi J, Qin L, Tian LQ, Guo FJ. LY294002 induces G0/G1 cell cycle arrest and apoptosis of cancer stem-like cells from human osteosarcoma via down-regulation of PI3K activity. Asian Pac J Cancer Prev. 2012;13(7):3103-7.

[7] Jung DW, Oh ES, Park SH, Chang YT, Kim CH, Choi SY, Williams DR. A novel zebrafish human tumor xenograft model validated for anti-cancer drug screening. Mol Biosyst. 2012 Jul 6;8(7):1930-9.

[8] Fang S, Wan X, Zou X, Sun S, Hao X, Liang C, Zhang Z, Zhang F, Sun B, Li H, Yu B. Arsenic trioxide induces macrophage autophagy and atheroprotection by regulating ROS-dependent TFEB nuclear translocation and AKT/mTOR pathway. Cell Death Dis. 2021 Jan 18;12(1):88.