957054-30-7

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.

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

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

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).

PI3Kα

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

1) Folkes?et al.?(2008),?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.?Med. Chem.,?51?5522 2) Raynaud?et al. (2009),?Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinase: from PI-103 through PI-540, PI620 to the oral agent GDC-0941; Mol. Cancer Ther.,?8?1725 3) Knapp et al. (2013),?A public-private partnership to unlock the untargeted kinome; Nat. Chem. Biol.,?9?3 4) Sarker?et al. (2015),?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; Clin. Cancer Res.,?21?77