| Identification | Back Directory | [Name]
PF-05212384 | [CAS]
1197160-78-3 | [Synonyms]
PKI587
PF-05212384
PF-05212384 (PKI-587)
PKI-587 ( Gedatolisib )
Gedatolisib (PF-05212384, PKI-587)
1-(4-(4-(Dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl
1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea
N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea PF-05212384 (PKI-587)
PKI-587 N-[4-[[4-(Dimethylamino)-1-piperidinyl]carbonyl]phenyl]-N'-[4-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]phenyl]urea | [Molecular Formula]
C32H41N9O4 | [MDL Number]
MFCD16875679 | [MOL File]
1197160-78-3.mol | [Molecular Weight]
615.726 |
| Chemical Properties | Back Directory | [Melting point ]
226-227°C | [density ]
1.364 | [storage temp. ]
Refrigerator | [solubility ]
DMSO | [form ]
Solid | [pka]
13.97±0.70(Predicted) | [color ]
Off-White | [InChIKey]
DWZAEMINVBZMHQ-UHFFFAOYSA-N | [SMILES]
N(C1=CC=C(C(N2CCC(N(C)C)CC2)=O)C=C1)C(NC1=CC=C(C2=NC(N3CCOCC3)=NC(N3CCOCC3)=N2)C=C1)=O |
| Hazard Information | Back Directory | [Chemical Properties]
Off-White Solid | [Uses]
This compound shows inhibitory activity against PI3K-α, PI3K-γ and mTOR. | [Biological Activity]
pf-05212384 is an inhibitor of pi3k/mtor with ic50 values of 0.4nm, 6nm, 8nm, 6nm and 1.4nm for pi3kα, pi3kβ, pi3kγ, pi3kδ and mtor, respectively [1].pf-05212384 is a pan-pi3k/mtorinhibitor and shows to be highly selective for pi3k and mtor. besides the wt p13k, pf-05212384 can also inhibit mutant p13k with ic50 values of 0.6nm for both h1047r and e545k mutants. in cellular assay, pf-05212384 potently inhibits tumor growth in mda-361 and pc3-mm2 cell lines with ic50 values of 4nm and 13.1nm, respectively. meanwhile, pf-05212384 suppresses the phosphorylation of pi3k/mtor signaling pathway proteins in cells. it inhibits the phosphorylation of akt as well as the akt effector proteins including gsk3 kinase, enos and pras 40. moreover, pf-05212384 has potent anti-tumor activity in a variety of xenograft models including h1975, bt474, hct116, h1975 and u87mg [1, 2] | [Synthesis]
The general procedure for the synthesis of 1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenyl)urea from 4-dimethylaminopiperidine and 4-(3-(4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenyl)urea was carried out in the following manner: first, at 50 °C, a mixture of 1-(4-(4-(dimethylamino)piperidin-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenyl)urea was added to 4-(3-(4-(4-(4,6-dimorpholin-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (45.5 g, 0.09 mol) in a slurry of anhydrous THF (1.6 L) was added to N,N'-carbonyldiimidazole (28 g, 0.17 mol). The reaction mixture was heated for 2 h. 4-Dimethylaminopiperidine (23.5 g, 0.18 mol) was added and stirred for 16 h at 53°C. After completion of the reaction, the mixture was cooled to room temperature and filtered. The filter cake was washed with 2-propanol and dried over air to give a white powder of 97% purity in 88% yield (49.2 g, 0.08 mol). Subsequently, the solid was dissolved in dimethylacetamide (DMAC, 165 ml) at 70 °C with stirring for 1 h. 2-Propanol (640 ml) was added and stirring was continued for 1 h at 65 °C. The resulting solid was filtered, washed with 2-propanol and finally dried in a vacuum oven at 70 °C for 16 h to obtain a crystalline white powder (45 g) of >99% purity. After the above post-treatment and crystallization process, the product had a Pd residue content of 20 ppm. | [Enzyme inhibitor]
This dual PI3K/mTOR (phosphoinositide-3-kinase and mammalian target of rapamycin) signal-transduction pathway inhibitor and antineoplastic agent (F.Wt. = 615.73; CAS 1197160-78-3); Solubility (25°C): 2 mg/mL DMSO, <1 mg/mL Water), also known as PF-05212384 and systematically as 1-(4- (4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino- 1,3,5-triazin-2-yl)phenyl)urea, inhibits PI3K-α, PI3K-γ and mTOR with IC50 of 0.4 nM, 5.4 nM and 1.6 nM, respectively. PKI-587 also inhibits mutant forms of PI3Kα, including the PI3Kα-H1047R and PI3Kα-E545K with IC50 of 0.6 nM and 0.6 nM, respectively. | [in vivo]
Gedatolisib (PKI-587; administered i.v. at 20 mg/kg on days 1, 5, 9) exhibits potent antitumor efficacy against MDA-361 tumors in mice[1].
Gedatolisib exhibits terminal elimination half-life (T1/2 14.4 h) due to high plasma clearance (7 mL/min/kg) combined with large volumes of distribution (7.2 L/kg respectively) following i.v. administration (25 mg/kg) female nude mice[1]. | Animal Model: | Female nude mice bearing MDA-361 xenograft model[1]. | | Dosage: | 20 mg/kg | | Administration: | Administered i.v. at 20 mg/kg on an intermittent regimen (days 1, 5, 9). | | Result: | Caused regression of large staged (~900 mm3) tumors.
The minimum efficacious dose (MED) was determined to be 3 mg/kg against MDA-361 tumors and maximum tolerated single dose (MTD) was determined to be 30 mg/kg. |
| [IC 50]
PI3Kα: 0.4 nM (IC50); PI3Kα-H1047R: 0.6 nM (IC50); PI3Kα-E545K: 0.6 nM (IC50); PI3Kγ: 5.4 nM (IC50); PI3Kβ: 6 nM (IC50); PI3Kδ: 6 nM (IC50); mTOR: 1.6 nM (IC50); mTORC1; mTORC2 | [storage]
Store at -20°C | [References]
[1] venkatesan a m, dehnhardt c m, delos santos e, et al. bis (morpholino-1, 3, 5-triazine) derivatives: potent adenosine 5′-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (pki-587), a highly efficacious dual inhibitor. journal of medicinal chemistry, 2010, 53(6): 2636-2645.
[2] mallon r, feldberg l r, lucas j, et al. antitumor efficacy of pki-587, a highly potent dual pi3k/mtor kinase inhibitor. clinical cancer research, 2011, 17(10): 3193-3203. |
| Questions And Answer | Back Directory | [Description]
Gedatolisib (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. |
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