Description
PI-103 (371935-74-9) is a potent inhibitor of PI-3 kinase, mTOR and DNA-PK, IC50 = 8, 88, 150, 48, 20, 83 and 2 nM for p110α, p110, p110γ, p110δ, mTORC1, mTORC2 and DNA-PK respectively.1,2 Synergizes with arsenic disulfide to eradicate AML stem cells by induction of differentiation.3 Inhibits the growth of gefitinib-resistant non-small cell lung cancer cell lines.4 Induces autophagy in drug-resistant glioma.5 Protects against a-synuclein-induced toxicity in human neurons by induction of macroautophagy.6
Uses
PI 103 is a dual inhbitor of Class IA phosphatidylinositol 3-kinase and mammalian target of rapaymycin complex 1 (mTORC1), both of which are involved in pathways often activated in myelogenous leukemia. PI 103 also functions to enhance tumour radiosensitivity.
Definition
ChEBI: An organic heterotricyclic compound that is pyrido[3',2':4,5]furo[3,2-d]pyrimidine substituted at positions 2 and 4 by 3-hydroxyphenyl and morpholin-4-yl groups respectively. A dual-kinase inhibitor with anti-cancer properties.
General Description
A cell-permeable pyridinylfuranopyrimidine compound that acts as a potent and ATP-competitive inhibitor of DNA-PK, PI3-K, and mTOR (IC
50 = 2, 8, 88, 48, 150, 26, 20, and 83 nM for DNA-PK, p110α, p110β, p110δ, p110γ, PI3-KC2β, mTORC1, and mTORC2, respectively). It inhibits ATR and ATM only at much higher concentrations (IC
50 = 850 and 920 nM, respectively) and exhibits little activity towards a panel of more than 40 other kinases even at concentrations as high as 10 μM. Shown to effectively block PI3-K/Akt signaling and cell proliferation in glioma cell lines both
in vitro and
in vivo. A 10 mM (2 mg/574 μl) solution of PI-103 (Cat. No.
528101) in DMSO is also available.
Biological Activity
Inhibitor of DNA-PK, PI 3-kinase (p110 α ) and mTOR (IC 50 values are 2, 8, 20, 26, 48, 83, 88, 150, 850, 920, ~ 1000 and 2300 nM for DNA-PK, p110 α , mTORC1, PI3KC2 β , p110 δ , mTORC2, p110 β , p110 γ , ATR, ATM, PI3KC2 α and hsVPS34 respectively). Inhibits growth of human tumor xenografts in mice in vivo .
Biochem/physiol Actions
Cell permeable: yes
target
Cell, 2013, 153(4):840-54
References
[1] ZACHARY A KNIGHT. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling.[J]. Cell, 2006, 125 4: 733-747. DOI:
10.1016/j.cell.2006.03.035[2] FLORENCE I RAYNAUD. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases.[J]. Cancer research, 2007, 67 12: 5840-5850. DOI:
10.1158/0008-5472.can-06-4615[3] ZHENYA HONG. Arsenic disulfide synergizes with the phosphoinositide 3-kinase inhibitor PI-103 to eradicate acute myeloid leukemia stem cells by inducing differentiation.[J]. Carcinogenesis, 2011, 32 10: 1550-1558. DOI:
10.1093/carcin/bgr176[4] ZU-QUAN ZOU. A novel dual PI3Kalpha/mTOR inhibitor PI-103 with high antitumor activity in non-small cell lung cancer cells.[J]. International journal of molecular medicine, 2009, 24 1: 97-101. DOI:
10.3892/ijmm\_00000212[5] QI-WEN FAN. Akt and Autophagy Cooperate to Promote Survival of Drug-Resistant Glioma[J]. Science Signaling, 2010, 3 147. DOI:
10.1126/scisignal.2001017[6] MATTHIAS HÖLLERHAGE . Multiple molecular pathways stimulating macroautophagy protect from alpha-synuclein-induced toxicity in human neurons[J]. Neuropharmacology, 2019, 149: Pages 13-26. DOI:
10.1016/j.neuropharm.2019.01.023
