PF-05212384

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.

Chemical Properties

Off-White Solid

Uses

This compound shows inhibitory activity against PI3K-α, PI3K-γ and mTOR. Potent PI3K/mTOR Dual Inhibitor.

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.

in vivo

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.

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.