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PIK-90

MCE China：PIK-90

Brand：MedChemExpress (MCE)

Cat. No.HY-12030

CAS：677338-12-4

Purity：99.61%

Storage：Powder -20°C 3 years 4°C 2 years In solvent -80°C 2 years -20°C 1 year

Shipping：Room temperature in continental US; may vary elsewhere.

Description：PIK-90 is a DNA-PK and PI3K inhibitor, which inhibits p110α, p110γ and DNA-PK with IC50s of 11, 18 and 13 nM, respectively.

In Vitro：PIK-90 also inhibits p110β, p110δ, PI3KC2α, PI3KC2β, hsVPS34, PI4KIIIα, PI4KIIIβ, ATR, ATM and mTORC1 with IC50s of 350 nM, 58 nM, 47 nM, 64 nM, 830 nM, 830 nM, 3.1 μM, 15 μM, 610 nM and 1.05 μM, respectively[1]. To determine the effects of PIK-90 on chronic lymphocytic leukemia (CLL) cell viability, CLL cells from different patients are incubated with various concentrations of PIK-90 (1 μM and 10 μM) for 24, 48, and 72 hours. PIK-90 reveals the strong apoptosis-inducing effects at both concentrations and at all different time points. Using a concentration of 10 μM, PIK-90 reduces the viability of CLL cells to 51.1% plus or minus 6.6% at 24 hours, whereas 1 μM PIK-90 reduces the viability to 77.8% plus or minus 6.4%[2].

In Vivo：To test the efficacy of Roscovitine and PIK-90 in vivo, GBM43 cells are implanted s.c. into nude mice. Mice with established tumors are randomized into four treatment groups: vehicle (PBS:H2O), Roscovitine, PIK-90, or PIK-90 plus Roscovitine. After 12 d of treatment, both Roscovitine and PIK-90 show clear single-agent efficacy, with tumor size in mice treated with Roscovitine and PIK-90 in combination significantly smaller than either vehicle or monotherapy-treated controls. Roscovitine is less effective than PIK-90 in blocking proliferation (levels of Ki-67), whereas combination therapy shows essentially additive antiproliferative effects[3].

Animal Administration：Mice[3] Human primary GBM43 cells (106) are injected s.c. just caudal to the left forelimb in 4- to 6-wk-old female BALB/c nu/nu mice. After tumors are established (50-100 mm3), mice are randomly allocated to daily i.p. treatment with 40 mg/kg PIK-90 (DMSO:H2O), 50 mg/kg Roscovitine (DMSO:PBS), 40 mg/kg PIK-90 plus 50 mg/kg Roscovitine, and DMSO:H2O:PBS (control). Tumor diameters are measured with calipers at 3-d intervals, and volumes are calculated.

Cell Assay：To determine the viability of CLL B cells, 200 μL cells are removed from the wells of a 24-well plate at the indicated time points and incubated for 15 minutes in fluorescence-activated cell sorter buffer (RPMI+0.5% BSA) containing 40 nM 3,3′-dihexyloxacarbocyanine iodide (DiOC6) and 10 μg/mL Propidium iodide (PI). Within 30 minutes, the cells are then analyzed by flow cytometry. Viable cells show high DiOC6 and low PI fluorescence, whereas apoptotic cells have low DiOC6 and PI fluorescence; necrotic cells are characterized by low DiOC6 and high PI fluorescence. The normal PBMCs are also cultured under the same conditions, with or without the various PI3K inhibitors (e.g., PIK-90, 1 μM and 10 μM), Fludarabine, and with or without stromal cell support, and their viability is also determined by staining with DiOC6 and PI[2].

IC50 & Target：p110α 11 nM (IC50) p110γ 18 nM (IC50) p110δ 58 nM (IC50) p110β 350 nM (IC50) hsVPS34 830 nM (IC50) PI3KC2β 64 nM (IC50) PI3KC2α 47 nM (IC50) DNA-PK 13 nM (IC50) ATM 610 nM (IC50) PI4KIIIα 830 nM (IC50) PI4KIIIβ 3.1 μM (IC50) mTORC1 1.05 μM (IC50) ATR 15 μM (IC50)

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References：

[1]. 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.  [Content Brief]

[2]. Niedermeier M, et al. Isoform-selective phosphoinositide 3'-kinase inhibitors inhibit CXCR4 signaling and overcome stromal cell-mediated drug resistance in chronic lymphocytic leukemia: a novel therapeutic approach. Blood. 2009 May 28;113(22):5549-57.  [Content Brief]

[3]. Cheng CK, et al. Dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma. Proc Natl Acad Sci U S A. 2012 Jul 31;109(31):12722-7.  [Content Brief]