Gedatolisib

Off-White SolidGedatolisib (PF-05212384, PKI-587) is a highly potent dual inhibitor of PI3Kα, PI3Kγ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM in cell-free assays, respectively. Phase 2.

Gedatolisib has been used in trials studying the basic science and treatment of Neoplasm, Ovary Cancer, Breast Cancer, Advanced Cancer, and Endometrial Cancer, among others.|Gedatolisib is an agent targeting the phosphatidylinositol 3 kinase (PI3K) and mammalian target of rapamycin (mTOR) in the PI3K/mTOR signaling pathway, with potential antineoplastic activity. Upon intravenous administration, gedatolisib inhibits both PI3K and mTOR kinases, which may result in apoptosis and growth inhibition of cancer cells overexpressing PI3K/mTOR. Activation of the PI3K/mTOR pathway promotes cell growth, survival, and resistance to chemotherapy and radiotherapy; mTOR, a serine/threonine kinase downstream of PI3K, may also be activated independent of PI3K.

To a slurry of 4-(3-(4-(4, 6-dimorpholin-4-yl-1, 3, 5-triazine-2-yl)phenyl)ureido)benzoic acid (7, 45.5 g, 0.09 mol) in dry THF (1.6 L) heated to 50 0.43 g of 4-(4, 6-dimorpholino-1, 3, 5-triazin-2-yl)aniline (1.26 mmol) was dissolved in 5 mL of DMF, then 0.23 g of pyridine (3 mmol) was added and placed In the ice bath, the temperature is below 5 ° C, 0.18 g of phenyl chloroformate (1.15 mmol) dissolved in 3 mL of DMF was added dropwise. After the addition is completed, The reaction was carried out at room temperature. After completion of the reaction, 0.27 g of (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (1.1 mmol) was added, and the mixture was heated to 90 ° C for 12 h.After the reaction was completed, the reaction solution was poured into 50 mL of water, a large amount of solid was precipitated, stirred for 20 min, and suction filtered to give a solid.0.2g. The purification was carried out by column chromatography, and the mobile phase was obtained by DCM: methanol: methanol ammonia solution = 10:1: 0.2, and finally, 0.11 g of solid was obtained, yield 17.8percent.0.46 g of phenyl(4-(4, 6-dimorpholino-1, 3, 5-triazin-2-yl)phenyl)carbamate (0.99 mmol)And 0.24 g of (4-aminophenyl)(4-(dimethylamino)piperidin-1-yl)methanone (0.97 mmol) were dissolved in 5 mL of DMF and heated to 90 ° C for 12 h.After the reaction was completed, the reaction solution was poured into 25 mL of water, a large amount of solid was precipitated, stirred for 20 min, and suction filtered to give a solid.0.4g. Purification using column chromatography, mobile phase using DCM: methanol:Methanol ammonia solution = 10:1:0.2, Finally, 0.1 g of solid is obtained.The yield was 16.3percent.

This compound shows inhibitory activity against PI3K-α, PI3K-γ and mTOR.

Molecular Weight:615.7
XLogP3:2.4
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:10
Rotatable Bond Count:7
Exact Mass:615.32815082
Monoisotopic Mass:615.32815082
Topological Polar Surface Area:128
Heavy Atom Count:45
Complexity:913
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes