PI-103 Hydrochloride is a dual PI3K and mTOR inhibitor with IC₅₀s of 8 nM, 88 nM, 48 nM, 150 nM, 20 nM, and 83 nM for p110α, p110β, p110δ, p110γ, mTORC1, and mTORC2. PI-103 Hydrochloride also inhibits DNA-PK with an IC50 of 2 nM. PI-103 Hydrochloride induces autophagy^[1][2][3][4].

PI-103 exhibits antiproliferative properties in a panel of human cancer cell lines^[1]. PI-103 is essentially cytostatic for cell lines and induced cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibits leukemic proliferation, the clonogenicity of leukemic progenitors and induces mitochondrial apoptosis, especially in the compartment containing leukemic stem cells ^[2]. PI-103 potently inhibits both the rapamycin-sensitive (mTORC1, IC₅₀=20 nM) and rapamycin-insensitive (mTORC2, IC₅₀=83 nM) complexes of the protein kinase mTOR^[4].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

PI-103 shows therapeutic activity against a range of human tumor xenografts, exhibiting inhibition of angiogenesis, invasion, and metastasis, as well as direct antiproliferative effects^[1]. PI-103 induces immunosuppression promoting in vivo tumor growth and inhibiting apoptosis. Tumors from PI-103-treated mice shows higher levels of cyclin D1 and more proliferating cells^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

384.82

C₁₉H₁₇ClN₄O₃

371935-79-4

Room temperature in continental US; may vary elsewhere.

4°C, sealed storage, away from moisture

*In solvent : -80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)

In Vitro: 

DMSO : 4.1 mg/mL (10.65 mM; Need ultrasonic and warming)

H₂O : < 0.1 mg/mL (ultrasonic;warming;heat to 60°C) (insoluble)

*

请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。
储备液的保存方式和期限：-80°C, 6 months; -20°C, 1 month (sealed storage, away from moisture)。-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。

• [1]. Raynaud FI, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther. 2009 Jul;8(7):1725-38.

  [2]. Knight ZA, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47.

  [3]. Park S, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase anLeukemia. 2008 Sep;22(9):1698-706.d mTOR, has antileukemicactivity in AmL. Leukemia. 2008 Sep;22(9):1698-706.

  [4]. López-Fauqued M, et al. The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int J Cancer. 2010 Apr 1;126(7):1549-61.

IC₅₀ values are measured using either a standard thin-layer chromatography (TLC) assay for lipid kinase activity or a high-throughput membrane capture assay. Kinase reactions are performed by preparing a reaction mixture containing kinase, inhibitor (2% DMSO final concentration), buffer (25 mM HEPES, pH 7.4, 10 mM MgCl₂), and freshly sonicated phosphatidylinositol (100 μg/mL). Reactions are initiated by the addition of ATP containing 10 μCi of γ-32P-ATP to a final concentration 10 or 100 μM, and allowed to proceed for 20 minutes at room temperature. For TLC analysis, reactions are then terminated by the addition of 105 μL 1N HCl followed by 160 μL CHCl₃:MeOH (1:1). The biphasic mixture is vortexed, briefly centrifuged, and the organic phase transferred to a new tube using a gel loading pipette tip precoated with CHCl₃. This extract is spotted on TLC plates and developed for 3-4 hours in a 65:35 solution of n-propanol:1M acetic acid. The TLC plates are then dried, exposed to a phosphorimager screen, and quantitated. For each compound, kinase activity is typically measured at 10-12 inhibitor concentrations representing two-fold dilutions from the highest concentration tested (100 μM). For compounds showing significant activity, IC₅₀ determinations are repeated two to four times, and the reported value is the average of these independent measurements^[4].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

For proliferation assays, MOLM14, OCI-AmL3 and MV4-11 cells are cultured during 48 h at 10⁵ cells/mL, in triplicate, in 10% FCS, without or with 0.1 or 1 μM PI-103, and then pulsed 6 h with 1μCi (37 kBq) [³H]-thymidine. The amounts of radioactivity are determined after trichloracetic acid precipitation^[2].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

Mice^[3]
Five to six month old males of either FVB/N strain or nude BALB/c strain are injected subcutaneously with one million cells in PBS. When tumor reaches between 50 and 100 mm³, mice are treated with 10 mg/kg or 70 mg/kg of PI-103 and/or 50 mg/kg sorafenib by IP injection daily. Control mice are treated with the same volume of DMSO. Tumor size and mice weight is monitored every 2 days. When mice are sacrificed, tumors are dissected and processed^[3].

上海金畔生物科技有限公司 has not independently confirmed the accuracy of these methods. They are for reference only.

• [1]. Raynaud FI, et al. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103through PI-540, PI-620 to the oral agent GDC-0941. Mol Cancer Ther. 2009 Jul;8(7):1725-38.

  [2]. Knight ZA, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47.

  [3]. Park S, et al. PI-103, a dual inhibitor of Class IA phosphatidylinositide 3-kinase anLeukemia. 2008 Sep;22(9):1698-706.d mTOR, has antileukemicactivity in AmL. Leukemia. 2008 Sep;22(9):1698-706.

  [4]. López-Fauqued M, et al. The dual PI3K/mTOR inhibitor PI-103 promotes immunosuppression, in vivo tumor growth and increases survival of sorafenib-treated melanoma cells. Int J Cancer. 2010 Apr 1;126(7):1549-61.