INK1117

INK1117 Property

Density 

1.55±0.1 g/cm3(Predicted)

storage temp. 

Store at -20°C

solubility 

≤1mg/ml in DMSO;0.25mg/ml in dimethyl formamide

form 

crystalline solid

pka

4.75±0.50(Predicted)

color 

White to gray

Hazard and Precautionary Statements (GHS)

Symbol(GHS)

Signal word

Warning

Hazard statements

H302Harmful if swallowed

H315Causes skin irritation

H319Causes serious eye irritation

H335May cause respiratory irritation

Precautionary statements

P261Avoid breathing dust/fume/gas/mist/vapours/spray.

P264Wash hands thoroughly after handling.

P264Wash skin thouroughly after handling.

P270Do not eat, drink or smoke when using this product.

P271Use only outdoors or in a well-ventilated area.

P280Wear protective gloves/protective clothing/eye protection/face protection.

P301+P312IF SWALLOWED: call a POISON CENTER or doctor/physician IF you feel unwell.

P302+P352IF ON SKIN: wash with plenty of soap and water.

P304+P340IF INHALED: Remove victim to fresh air and Keep at rest in a position comfortable for breathing.

P305+P351+P338IF IN EYES: Rinse cautiously with water for several minutes. Remove contact lenses, if present and easy to do. Continuerinsing.

P321Specific treatment (see … on this label).

P330Rinse mouth.

P332+P313IF SKIN irritation occurs: Get medical advice/attention.

P337+P313IF eye irritation persists: Get medical advice/attention.

P403+P233Store in a well-ventilated place. Keep container tightly closed.

P405Store locked up.

P501Dispose of contents/container to..…

INK1117 Chemical Properties,Usage,Production

Uses

INK1117 is an inhibitor of phosphoinositide 3-kinase α (PI3Kα) that is selective for p110α in vitro (IC50 = 15 nM for PI3Kα vs. >1 μM for other isoforms, as well as for mTOR) and in cells when used at 1 μM. It blocks signaling to Akt and inhibits growth of cancer cells harboring wild-type or mutated p110α. INK1117 does not interfere with B cell proliferation or NK cell maturation and survival.[Cayman Chemical]

Uses

MLN 1117 is an inhibitor of PI3Kα which is selective for p110α in vitro. Useful in the attenuation of cell proliferation.

Biological Activity

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.

Synthesis

1. assemble a 5L three-necked, round-bottomed flask equipped with a mechanical stirrer, thermocouple probe, nitrogen/vacuum inlet, and reflux condenser, and place in a heating jacket. 2. add 1,4-dioxane (3.75 L) and water (1.25 L) to the flask at room temperature. 3. (2-Amino-1,3-benzoxazol-5-yl)boronic acid hydrochloride (250 g) and (6-bromo-5H-imidazo[2,1-b][1,3]oxazin-3-yl)(morpholinyl)methanone (210 g) were added sequentially at room temperature. 4. The reaction mixture was stirred at room temperature for 10 minutes. 5. Sodium carbonate (300 g) was added followed by Pd(PPh3)4 (47 g) at room temperature. 6. the reactor was sprayed with nitrogen for about 30 minutes under stirring to deoxygenate the reaction mixture by 5 to 6 vacuum/nitrogen cycles. 7. The reaction mixture was heated to reflux (88 °C to 102 °C) and stirred for 5 to 8 hours under light nitrogen bubbling. 8. The progress of the reaction was monitored by HPLC. 9. Upon completion of the reaction, the reaction mixture was cooled to 75-80°C. 10. 10. Water (3.75 L) and ethyl acetate (1.25 L) were added at 75-80 °C. 11. The mixture was cooled to room temperature and stirred for 2 hours. 12. The mixture was filtered and the collected solid was washed sequentially with water (2 x 1.25 L), methanol (1.25 L) and ethyl acetate (2 x 1.25 L). 13. Suspend the solid in ethyl acetate (1.5L) for 1 hour at room temperature. 14. Filtered the suspension and washed the solid with ethyl acetate (250mL). 15. Repeat steps 13 and 14 twice. 16. The solid obtained was dried under vacuum to obtain the crude product (250 g, 85% yield; HPLC purity 98.1%; Pd content 1831 ppm). 17. Purification of crude product: the crude product (250 g) was suspended in methanol (2.5 L) and HCl (158 mL) at room temperature. 18. The mixture was heated to 40 to 45°C to form a slightly turbid solution. 19. Charcoal (250 g) was added and stirred at 40 to 45°C for 30 minutes. 20. The hot solution was filtered through a polymer pad fitted with a 2-inch bed of diatomaceous earth, and the filter cake was washed with methanol (3 x 500 mL). 21. The filtrate was refilled into a flask (Pd content: 330 ppm). 22. the solution was heated to 40 to 45 °C and charcoal (50 g) and silica thiols (50 g) were added. 23. After stirring at 40 to 45°C for 30 minutes, the hot solution was filtered through a polymer pad and the filter cake was washed with methanol (250 mL). 24. Steps 22 and 23 were repeated once. 25. Concentrate under vacuum at 30 to 35°C to about 2.5L. 26. The solution was cooled to 10 to 15 °C and the pH was adjusted to 8-9 by adding concentrated ammonia solution (200 mL). 27. cool the reaction mixture to 0 to 5°C and stir for 1 to 2 hours. 28. The mixture was filtered and the filter cake was washed sequentially with water (2 x 500 mL) and methanol (2 x 500 mL). 29. Transfer the solid to a round bottom flask and suspend in ethyl acetate (2.5 L) for 2 to 3 hours at room temperature. 30. The solid was collected by filtration and washed with ethyl acetate (750mL). 31. The solid was dried under vacuum at about 50 °C to constant weight to afford the target compound (180 g, 61% yield; HPLC purity 98.5%; 1H NMR (DMSO-d6, 300 MHz) δ 9.1 (s, 1H), 8.1 (s, 1H), 7.8-7.65 (m, 2H), 7.60-7.40 (m, 4H), 7.3- 7.2 (m, 1H), 3.8-3.6 (m, 8H); 1 ppm Pd.

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].

IC 50

15nm: inhibits phosphoinositide 3-kinase α (pi3kα) in vitro.

References

[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.