PIK-75

Names

[ Name ]:
PIK-75

[Synonym ]:
2-methyl-5-nitro-2,3-dihydro-phthalazine-1,4-dione
N'-[(E)-(6-Bromoimidazo[1,2-a]pyridin-3-yl)methylene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide
Benzenesulfonic acid, 2-methyl-5-nitro-, 2-[(1E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide
2-Methyl-5-nitro-2,3-dihydro-phthalazin-1,4-dion
2-methyl-5-nitro-2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazidebenzenesulfonic acid
8-Nitro-3-methyl-2,3-dihydro-1,4-phthalazindion
[2-methyl-5-nitro-1-benzenesulfonic acid 2-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylene]-1-methylhydrazide]
1,4-Phthalazinedione,2,3-dihydro-2-methyl-5-nitro
N'-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide
2'-[(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-1',2-dimethyl-5-nitrobenzenesulfonohydrazide
PIK-75 free base

Biological Activity

[Description]:

PIK-75 is a reversible DNA-PK and p110α-selective inhibitor, which inhibits DNA-PK, p110α and p110γ with IC50s of 2, 5.8 and 76 nM, respectively. PIK-75 inhibits p110α >200-fold more potently than p110β (IC50=1.3 μM)[1][2]. PIK-75 induces apoptosis[3].

[Related Catalog]:

Signaling Pathways >> Apoptosis >> Apoptosis

Research Areas >> Cancer

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA-PK

Signaling Pathways >> PI3K/Akt/mTOR >> PI3K

Signaling Pathways >> PI3K/Akt/mTOR >> DNA-PK

[Target]

DNA-PK:2 nM (IC50)

p110α:5.8 nM (IC50)

p110γ:76 nM (IC50)

p110δ:510 nM (IC50)

p110β:1.3 μM (IC50)

hsVPS34:2.6 μM (IC50)

PI3KC2β:1 μM (IC50)

PI3KC2α:10 μM (IC50)

mTORC1:1 μM (IC50)

mTORC2:10 μM (IC50)

ATM:2.3 μM (IC50)

ATR:21 μM (IC50)

PI4KIIIβ:50 μM (IC50)

[In Vitro]

PIK-75 also inhibits p110δ, PI3KC2β, mTORC1, ATM, hsVPS34, PI3KC2α, mTORC2, ATR and PI4KIIIβ with IC50s of 510 nM, ~1 μM, ~1 μM, 2.3 μM, 2.6 μM, ~10 μM, ~10 μM, 21 μM, ~50 μM, respectively[1]. PIK-75 alone blocks Thr 308 phosphorylation in L6 myotubes and 3T3-L1 adipocytes with IC50 values of 1.2 and 1.3 μM, respectively[1]. PIK-75 (1-1000 nM; 5 min) blocks the phosphorylation of PKB induced by insulin on both Ser473and Thr308 in CHO-IR cells in a dose-dependent manner, with an IC50 of 78 nM[2]. PIK-75 (0.1-1000 nM; 48 hours) inhibits the proliferation and survival of pancreatic cancer cells through apoptotic cell death[3]. PIK-75 (0.1-1000 nM) also reduces the colony formation of pancreatic cancer MIA PaCa-2 and AsPC-1 cells[3]. Cell Viability Assay[3] Cell Line: Human pancreatic cancer cells (MIA PaCa-2 or AsPC-1) Concentration: 0.1, 0.3, 1, 3, 10, 30, 100, 300, and 1000 nM Incubation Time: 48 hours Result: Submicromolar concentration was sufficient to inhibit the proliferation of pancreatic cancer, MIA PaCa-2 and AsPC-1 cells after 48-h treatment. Western Blot Analysis[2] Cell Line: Overnight-starved CHO-IR cells Concentration: 1, 10, 100, 1000 nM Incubation Time: 5 minutes Result: Blocked the phosphorylation of PKB induced by insulin (1 nM, 10 min) on both Ser473and Thr308 in a dose-dependent manner.PIK-75 potentiates anticancer activity of Gemcitabine (20 mg/kg) in vivo. Gemcitabine (20 mg/kg) or PIK-75 (2 mg/kg) alone reduces the tumor growth to similar degree. Beneficial effect of PIK-75/Gemcitabine is evident as this combination markedly reduces the tumor growth in vivowithout affecting the body weights of mice[3].

[In Vivo]

PIK-75 (2 mg/kg) potentiates anticancer activity of Gemcitabine (20 mg/kg) in vivo. Gemcitabine (20 mg/kg) or PIK-75 (2 mg/kg) alone reduces the tumor growth to similar degree. Beneficial effect of PIK-75/Gemcitabine is evident as this combination markedly reduces the tumor growth in vivowithout affecting the body weights of mice[3]. Animal Model: Mice bearing tumors of MIA PaCa-2[3] Dosage: 2 mg/kg; or combination with Gemcitabine (20 mg/kg) Administration: Administered injection; 5 times per week. 25 days Result: Reduced the tumor growth and enhanced the antitumor effect.

[References]

[1]. Knight ZA, et al. A pharmacological map of the PI3-K family defines a role for p110alpha in insulin signaling. Cell. 2006 May 19;125(4):733-47.

[2]. Chaussade C, et al. Evidence for functional redundancy of class IA PI3K isoforms in insulin signalling. Biochem J. 2007 Jun 15;404(3):449-58.

[3]. Duong HQ, et al. Inhibition of NRF2 by PIK-75 augments sensitivity of pancreatic cancer cells to gemcitabine. Int J Oncol. 2014 Mar;44(3):959-69.

Chemical & Physical Properties

[ Density]:
1.7±0.1 g/cm3

[ Molecular Formula ]:
C₁₆H₁₄BrN₅O₄S

[ Molecular Weight ]:
452.283

[ Exact Mass ]:
450.994965

[ PSA ]:
121.24000

[ LogP ]:
3.84

[ Index of Refraction ]:
1.701

Related Compounds

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