Pictilisib CAS 957054-30-7

Introduction：Basic information about Pictilisib CAS 957054-30-7, including its chemical name, molecular formula, synonyms, physicochemical properties, and safety information, etc.

Pictilisib Basic information

• Product Name: Pictilisib
• Synonyms: Pictilisib;Thieno[3,2-d]pyrimidine, 2-(1H-indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)-;GDC-0941;GDC-0941 free base;2-(1H-Indazol-4-yl)-6-[[4-(methylsulfonyl)-1-piperazinyl]methyl]-4-(4-morpholinyl)thieno[3,2-d]pyrimidine;GDC-0941 bismesylate;2-(1H-Indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine;4-(2-(1H-Indazol-4-yl)-6-((4-(Methylsulfonyl)piperazin-1-yl)Methyl)thieno[3,2-d]
• CAS: 957054-30-7
• MF: C23H27N7O3S2
• MW: 513.64
• EINECS: 1312995-182-4
• Product Categories: An inhibitor of class I PI3 kinase (PI3K).;Inhibitors;Akt;mTOR;PI3K
• Mol File: 957054-30-7.mol

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

• WGK Germany: WGK 3
• HS Code: 29350090
• Storage Class: 11 - Combustible Solids

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

885618-33-7

885675-66-1

957054-30-7

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

Pictilisib (GDC-0941) (150 mg/kg, p.o.) leads to tumor stasis in MCF7-neo/HER2-bearing animals model. Pictilisib (GDC-0941) and RP-56976 result in tumor regressions during the treatment period leading to enhanced antitumor responses^[1]. Tumours in the Pictilisib (GDC-0941)-treated mice show a marked non-linear shrinkage, and when the Pictilisib (GDC-0941) treatment ceased, the tumours in the test cohort mice grow again^[2]. Pictilisib (GDC-0941) (25 or 50 mg/kg) reduces tumor growth and PI3K and HIF-1 pathway activity in eGFP-FTC133 tumor-bearing mice^[4].

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

Pictilisib Preparation Products And Raw materials

• Raw materials: 4-(4,4,5,5-TETRAMETHYL-[1,3,2]DIOXABOROLAN-2-YL)-1H-INDAZOLE-->2-CHLORO-6-(4-METHANESULFONYL-PIPERAZIN-1-YLMETHYL)-4-MORPHOLIN-4-YL-THIENO[3,2-D]PYRIMIDINE-->Sodium bicarbonate-->Water-->Ethanol-->Toluene