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PF-05212384 (PKI-587)
Cat No.
CEI-0090
Description
As an ATP-competitive inhibitor, PKI-587 can potently inhibited PI3K-alpha and mTOR with of 0.4 nM and 1 nM.
CAS No.
1197160-78-3
Molecular Weight
615.73
Purity
>99%
Storage
2 years at -20 centigrade
Targets
PI3Kalpha, mTOR
Molecular Formula
C32H41N9O4
Chemical Name
1-(4-(4-(dimethylamino)piperidine-1-carbonyl)phenyl)-3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)urea
Solubility
DSMO 2 mg/mL Water
In vitro
As an ATP-competitive inhibitor, PKI-587 can potently inhibited PI3K-alpha and mTOR with of 0.4 nM and 1 nM, as PKI-587 is an equipotent PI3K-alpha/mTOR inhibitor. PKI-587 inhibit mutant forms of PI3K-alpha with similar IC50s.But for PI3K-beta, PI3K-delta, and PI3K-gamma, the IC50s are 10 times as Ic50 of PI3K-alpha.For cancer cell lines, PKI-587 inhibited growth of 50 diverse human tumor cell lines at IC50 values of less than 100 nM.PKI-587 suppressed phosphorylation of downstream effectors of PI3K signaling at concentrations that closely matched growth inhibition IC50 values in MDA-MB-361, BT474, HCT116, H1975, U87MG, and A498. PKI-587 can inhibit phosphorylation of PI3K and mTOR effector proteins. Besides above, PKI-587 can also cause potent suppression of p-Akt at S473. By inhibiting p-Akt, PKI-587 can cause consequent effects on Akt effectors such as PRAS40 (proline-rich Akt substrate), ENOS (endothelial nitric oxide synthase), and GSK3 (glycogen synthase kinase 3).
In vivo
In breast (MDA-MB-361, BT474), colon (HCT116), lung (H1975), and glioma (U87MG) xenograft models, PKI-587 shows anti-tumor effect.In MDA-MB-361 tumors, PKI-587 (25 mg/kg) suppress Akt phosphorylation and induce cleaved PARP (cPARP). In the MDA-MB-361 model, PKI-587 lead to tumor regression by suppression of phosphorylated Akt. In the U87MG glioblastoma multiforme xenograft model, PKI-587(25 mg/kg) can cause U87MG tumor regression.PKI-587 also caused regression in other tumor models, and efficacy was enhanced when given in combination with PD0325901 (MEK 1/2 inhibitor), irinotecan (topoisomerase I inhibitor), or HKI-272 (neratinib, HER2 inhibitor).
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