A selective inhibitor of PI3Kα
IC50: 15nM: inhibits phosphoinositide 3-kinase α (PI3Kα) in vitro.
INK1117 is a novel, potent and selective inhibitor of PI3Kα with potential antineoplastic activity, which may induce tumor cell apoptosis and growth inhibition in PI3Kα-expressing tumor cells. INK1117 dampens signaling to Akt and suppresses the growth of cancer cells harboring wild-type or mutated p110α. PI3Ks, a family of eight lipid kinase enzymes, produce 3-phosphorylated phosphoinositides in cellular membranes and are promising targets for therapeutic development in cancer.
In vitro: INK1117 blocked class I PI3K enzymes (p110α, p110β, p110γ or p110δ) in the low to mid-nanomolar range in human natural killer (NK) cell lines. INK1117 selectively inhibited PI3K signaling in cellular assays when used at 0.1-1 μM. INK1117 selectively dampened p110 α when used at 1 μM. INK1117 did not inhibit production of IFN-γ protein in cells with anti-NKG2D, indicating that INK1117 did not decrease IFN-γ mRNA [1].
In vivo: Female C57BL/6 mice were orally given INK1117 at a dose of 60 mg/kg using a sterile disposable 20G-1.5” feeding needle. After 8 days, INK1117 had negligible effects on NK cell maturation or survival. However, INK1117 did not show significantly decrease in the percentage of B cells and did not alter the percentages of T cells or the fractions of CD4 and CD8 T cells, the percentages of NK cells in bone marrow and spleen [1].
Reference:
[1].? Yea, S., So, L., Mallya, S., Lee, J., Rajasekaran, K., Malarkannan, S., & Fruman, D. Effects of Novel Isoform-Selective Phosphoinositide 3-Kinase Inhibitors on Natural Killer Cell Function. Plos ONE. 2014; 9(6): e99486.
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Cell experiment: |
A total of 5000 SK-OV-3 and U87MG cell lines/well in low serum media (0.2% FBS) are seeded in triplicate wells of a 96-well flat bottom culture plate for 18 h to adhere. Media is aspirated and inhibitors in 0.2% FBS media are added to each well at the indicated concentrations. After 48 h, cell viability is determined using the MTS assay (Cell Titer 96 Aqueous One solution cell proliferation assay kit) with absorbance (490 nm) measured in a microplate spectrophotometer[1]. |
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Animal experiment: |
Mice[1] Wild-type 8-week-old Balb/cJ mice are used for all experiments. Serabelisib and GDC-0941 are given by oral gavage using a sterile disposable 20-guage 1.5′ feeding needle. IC87114 is delivered via intraperitoneal injection. For the non-immunization experiment, 2 mice per group (Vehicle, GDC-0941, and Serabelisib (MLN1117)) are given the indicated drugs for 9 days before sacrificing on day 10. For the immunization experiment, 4 mice per group are used to perform two independent studies comparing GDC-0941 or IC87114 to Serabelisib (MLN1117). In all cases, the vehicle group receive both vehicles used to formulate the two different drugs. Mice are treated with the drugs throughout day -1 to day 13. On day 0, all mice are immunized with NP-OVA precipitated in alum. Drug treatment is stopped on day 13 and mice are sacrificed for collection of serum and spleens. |
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参考文献: [1]. So L, et al. Selective inhibition of phosphoinositide 3-kinase p110α preserves lymphocyte function. J Biol Chem. 2013 Feb 22;288(8):5718-31. |
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