| Identification | Back Directory | [Name]
PIK-III | [CAS]
1383716-40-2 | [Synonyms]
PIK-III
Vps34-PIK-III
Vps34 inhibitor PIK-III
4'-(Cyclopropylmethyl)-N2-4-pyridinyl[4,5'-bipyrimidine]-2,2'-diamine
[4,5'-Bipyrimidine]-2,2'-diamine, 4'-(cyclopropylmethyl)-N2-4-pyridinyl- | [Molecular Formula]
C17H17N7 | [MOL File]
1383716-40-2.mol | [Molecular Weight]
319.36 |
| Chemical Properties | Back Directory | [Boiling point ]
657.4±65.0 °C(Predicted) | [density ]
1.380±0.06 g/cm3(Predicted) | [storage temp. ]
Store at -20°C | [solubility ]
≥31.9 mg/mL in DMSO; insoluble in H2O; insoluble in EtOH | [form ]
solid | [pka]
6.19±0.26(Predicted) | [color ]
White to off-white |
| Hazard Information | Back Directory | [Uses]
Vps34-PIK-III is an orally active and selective VPS34 inhibitor (IC50=18 nM). Vps34-PIK-III effectively inhibits autophagy and can be used as a molecular tool. vps34-PIK-III is also a PI3K inhibitor that inhibits the expression of genes in liver cancer stem cells (CSCs)[1][2][3]. | [Biological Activity]
pik-iii is a vps34 inhibitor and is able to inhibit autophagy.vps34 kinase has been found to be responsible for synthesis and deposition of phosphatidylinositol-3-phosphate at autophagosome formation sites, resulting in the recruitment of ptdins(3)p-binding proteins. | [Synthesis]
Examples 10a-10v General method for the synthesis of 4'-(cyclopropylmethyl)-N-pyridin-4-yl-4,5'-bipyrimidinyl-2,2'-diamine. Preparation of 4'-(cyclopropylmethyl)-N-pyridin-4-yl-[4,5']bipyrimidinyl-2,2'-diamine (10a): to a (3Z)-1-cyclopropyl-4-(dimethylamino)-3-[2-(pyridin-4-ylamino)pyrimidin-4-yl]but-3-en-2-one (9) (80 mg, 0.247 mmol) of DMF (2.061 mL ) solution was added guanidine hydrochloride (35.3 mg, 0.371 mmol) and potassium carbonate (103 mg, 0.742 mmol) and the reaction mixture was heated at 60 °C for 4 hours. The crude product was purified by reversed-phase HPLC [30-90% organic phase over 15 min], followed by further purification using Biotage? silica gel chromatography [10 g SNAP column, 100% DCM to 12% MeOH/DCM] to afford the target product as a white solid (24.72 mg, 31.3% yield).1H NMR (400 MHz, MeOD) δ ppm 0.01-0.14 (m, 2H), 0.39 (q, J = 6.06 Hz, 2H), 0.94-1.10 (m, 1H), 2.87 (d, J = 7.07 Hz, 2H), 7.10 (d, J = 5.05 Hz, 1H), 7.83 (d, J = 6.57 Hz, 2H), 8.30 (d, J = 6.57 Hz , 2H), 8.41 (s, 1H), 8.57 (d, J = 5.05 Hz, 1H). HRMS (ES+) C17H17N7H+ [MH+] calculated value: 320.1624; measured value: 320.1636. UV-LC: 100% UV purity at 254/214 nm; tR = 4.67 min, total run time 7.75 min. | [in vitro]
in previous study, pik-iii was identified as a selective inhibitor of vps34 binding in a hydrophobic pocket. in addition, pik-iii could acutely inhibit the autophagy and lipidation of lc3, which led to the stabilization of autophagy substrates. moreover, substrates such as ncoa4 were identified by conducting ubiquitin-affinity proteomic assay on pik-iii-treated cells, which accumulated in cells with atg7 deficience and co-localized with autolysosomes. ncoa4 could bind ferritin heavy chain-1 directly to target the iron-binding ferritin complex following starvation or iron depletion [1]. | [in vivo]
animal study showed that pik-iii-treated ncoa4-/- mice had a profound accumulation of iron in splenic macrophages that were important for iron reutilization from engulfed red blood cells. in summary, such in vivo results provided a novel mechanism for selective autophagy of ferritin and revealed a previously untouched role for autophagy and ncoa4 in the control of in-vivo iron homeostasis [1]. | [IC 50]
18 nm for vps34 | [References]
[1] dowdle we et al. selective vps34 inhibitor blocks autophagy and uncovers a role for ncoa4 in ferritin degradation and iron homeostasis in vivo. nat cell biol. 2014 nov;16(11):1069-79. |
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