N-(2,3-Dihydro-7,8-dimethoxyimidazo[1,2-c]quinazolin-5-yl)-3-pyridinecarboxamide

Description

PIK-90 is a PI3Kα/γ/δ inhibitor with IC50 of 11 nM/18 nM/58 nM, respectively, less potent to PI3Kβ.

In vitro

PIK-90 shows distinct patterns of isoform selectivity to inhibit different subsets of four class I PI3K isoforms. In addition, PIK-90 completely inhibits the fMLP-stimulated phosphorylation of Akt and impairs polarity and chemotaxis in dHL60 cells. PIK-90 exhibits significantly antiproliferative activity by effectively blocking phosphorylation of Akt in six glioma cell lines varying in mutational status at PTEN or p53, including U87 MG, SF188, SF763, LN229, A1207 and LN-Z30 cells. Moreover, PIK-90 induces a modest G0G1 arrest at a concentration (0.5 μM) sufficient to inhibit phosphorylation of Akt substantially. In chronic lymphocytic leukemia (CLL) cells, PIK-90 inhibits chemotaxis to levels that are 57.8% of controls at 1 μM and 56.8% of controls at 10 μM. Consistently, PIK-90 inhibits pseudoemperipolesis to levels that are 74.2% PIK-90 of controls at 1 μM and 57.9% of controls at 10 μM. In addition, PIK-90 also leads to a significant reduction of CLL cell migration into the stromal cell layer and decreases CXCL12-induced actin polymerization.

In vivo

Immediately following insulin treatment, PIK-90 (10 mg/kg) completely protects animals from this insulin-stimulated decline in blood glucose.

Uses

PIK-90 is a PI3Kα/γ/δ inhibitor, less potent to PI3Kβ.

Definition

ChEBI: N-(7,8-dimethoxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)-3-pyridinecarboxamide is a member of quinazolines.

Biological Activity

pik-90 is a broad-spectrum pi3k inhibitors that inhibits pi3kα, pi3kγ and pi3kδ with ic50 values of 11, 18 and 58nm, respectively [1].studies showed that pik-90 induced increased levels of secreted ige at 1 μmol/l, while it inhibited ige production at doses of greater than 2 μmol/l [2]. pik-90 has been reported to block akt phosphorylation. pik-90 combined with the cdk2 inhibitor has been demonstrated to induce apoptosis in ln229 ptenwt cells. in addition, pik-90 combined with sirna against both cdk1 and cdk2 has shown to induce cell death, whereas pik-90 combined with sirna against cdk1 or cdk2 had no apoptotic effect [3].

in vivo

pik-90 combined with roscovitine revealed a significant reduction of tumor size in nude mice implanted with gbm43 cells [3].

target

p110α

storage

Store at -20°C

References

[1] van keymeulen a1, wong k, knight za, govaerts c, hahn km, shokat km, bourne hr. to stabilize neutrophil polarity, pip3 and cdc42 augment rhoa activity at the back as well as signals at the front. j cell biol. 2006 jul 31;174(3):437-45. epub 2006 jul 24.
[2] zhang tt1, okkenhaug k, nashed bf, puri kd, knight za, shokat km, vanhaesebroeck b, marshall aj. genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances ige production. j allergy clin immunol. 2008 oct;122(4):811-819.e2.
[3] cheng ck1, gustafson wc, charron e, houseman bt, zunder e, goga a, gray ns, pollok b, oakes sa, james cd, shokat km, weiss wa, fan qw. dual blockade of lipid and cyclin-dependent kinases induces synthetic lethality in malignant glioma. proc natl acad sci u s a. 2012 jul 31;109(31):12722-7.