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]
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
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.
