Pictilisib Chemical Properties

Melting point:

>200oC (dec.)

Density 

1.53±0.1 g/cm3(Predicted)

storage temp. 

-20°C

solubility 

Soluble in DMSO (>25 mg/ml)

form 

White powder solid.

pka

12.22±0.40(Predicted)

color 

White/off-white

Stability:

Stable for 1 year from date of purchase as supplied. Solutions in DMSO may be stored at -20°C for up to 3 months.

InChIKey

LHNIIDJUOCFXAP-UHFFFAOYSA-N

SMILES

C1(C2=CC=CC3=C2C=NN3)=NC(N2CCOCC2)=C2SC(CN3CCN(S(C)(=O)=O)CC3)=CC2=N1

Safety Information

HS Code 

29350090

Pictilisib Usage And Synthesis

Description

GDC-0941/Pictilisib (957054-30-7) is a potent and selective inhibitor of class I phosphatidylinositol-3-kinases (PI3K) with significant antitumor activity – IC50’s: PI3Kα = 3nM, PI3Kβ = 33 nM, PI3Kδ = 3 nM, PI3Kγ = 75 nM.1,2?? GDC-0941 is the chemical probe of choice for the pan-inhibition of class I PI3K’s.3?Currently in clinical trials.4

Uses

GDC-0941 is a potent and selective oral inhibitor of the class I PI3K. GDC-0941 demonstrated broad spectrum of activity in breast, ovarian, lung, and prostate cancer models. Studies has also shown GDC-0941 may enhance anti-tumor activity of Docetaxel (D494420) in human breast cancer models. Potent PI3K inhibitor.

Definition

ChEBI: A sulfonamide composed of indazole, morpholine, and methylsulfonyl-substituted piperazine rings bound to a thienopyrimidine ring.

Synthesis

Step 1: 4-(2-chloro-6-((4-(methylsulfonyl)piperazin-1-yl)methyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (Compound 0113, 800 mg, 1.86 mmol), pinacol ester of 1H-indazole-4-boronic acid (0107-3, 500 mg, 2.04 mmol), sodium bicarbonate (470 mg. 5.58 mmol), sodium bicarbonate (470 mg, 5.58 mmol), and bis(triphenylphosphine)palladium(II) chloride (80 mg, 0.093 mmol) were dissolved in a solvent mixture of toluene (20 mL), ethanol (12 mL), and water (5.6 mL). The reaction system was replaced by nitrogen and then heated at 120 °C for 1 h under microwave radiation. After completion of the reaction, the reaction mixture was partitioned between dichloromethane and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting crude product was purified by silica gel column chromatography (eluent: dichloromethane containing 2% methanol, v/v) to afford 2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (Compound 0114, 350 mg, 37% yield) as a white solid with a melting point of 148-149 °C. LC -MS: m/z 514 [M+H]+; 1H NMR (400 MHz, CDCl3): δ 2.70 (t, J = 4.4 Hz, 4H), 2.81 (s, 3H), 3.13 (t, J = 4.4 Hz, 4H), 3.92 (m, 6H), 4.09 (t, J = 5.6 Hz, 4H), 7.41 (s, 1H), 7.50 (m, 1H), 7.59 (d, J = 8.4 Hz, 1H), 8.28 (d, J = 6.8 Hz, 1H), 9.00 (s, 1H), 10.32 (br s, 1H).

in vivo

target

PI3Kα

IC 50

p110α: 3 nM (IC₅₀); p110α-H1047R: 3 nM (IC₅₀); p110α-E545K: 3 nM (IC₅₀); p110δ: 3 nM (IC₅₀); p110β: 33 nM (IC₅₀); p110γ: 75 nM (IC₅₀); mTOR: 0.58 μM (Ki); DNA-PK: 1.23 μM (IC₅₀); Autophagy

References

[1] ADRIAN J. FOLKES*. The Identification of 2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (GDC-0941) as a Potent, Selective, Orally Bioavailable Inhibitor of Class I PI3 Kinase for the Treatment of Cancer†[J]. Journal of Medicinal Chemistry, 2008, 51 18: 5522-5532. DOI:10.1021/jm800295d
[2] FLORENCE I RAYNAUD. Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941.[J]. Molecular Cancer Therapeutics, 2009, 8 7: 1725-1738. DOI:10.1158/1535-7163.mct-08-1200
[3] STEFAN KNAPP. A public-private partnership to unlock the untargeted kinome[J]. Nature chemical biology, 2012, 9 1: 3-6. DOI:10.1038/nchembio.1113
[4] DEBASHIS SARKER. First-in-human phase I study of pictilisib (GDC-0941), a potent pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor, in patients with advanced solid tumors.[J]. Clinical Cancer Research, 2015, 21 1: 77-86. DOI:10.1158/1078-0432.ccr-14-0947

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