Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors

Hayakawa, Masahiko; Kaizawa, Hiroyuki; Moritomo, Hiroyuki; Koizumi, Tomonobu; Ohishi, Takahide; Okada, Minoru; Ohta, Mitsuaki; Tsukamoto, Shin‐ichi; Parker, Peter J.; Workman, Paul; Waterfield, Mike

doi:10.1016/j.bmc.2006.06.046

Cited by 182 publications

(133 citation statements)

References 30 publications

Supporting

Mentioning

131

Contrasting

Order By: Relevance

“…Since there was a reduction in ARE-LUC activity in p110a siRNA-transfected cells, we used PI3K isoform-specific inhibitors to verify if p110b is unique for AR-mediated gene expression. The isoform specificity of the inhibitors, PI3K Inhibitor 4 (PI3K-I4) for p110a and TGX-221 for p110b, was described previously (Jackson et al, 2005;Hayakawa et al, 2006). The mRNA expression level of the well-known AR target psa gene was chosen to evaluate the effect of these inhibitors on androgen-stimulated AR transactivation.…”

Section: Resultsmentioning

confidence: 99%

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

et al. 2008

View full text Add to dashboard Cite

Phosphoinositide 3-OH kinases (PI3Ks) are a group of major intracellular signaling molecules. In our previous study, we found that inhibition of PI3K activity suppressed the androgen receptor (AR)-mediated gene expression in prostate cancer cells. The AR has been considered as a critical determinant for the development and progression of human prostate cancers. In this study, we sought to identify the PI3K isoforms involved in AR transactivation. Using a gene-specific small interference RNA (siRNA) approach, we determined that the regulatory isoform p85a and the catalytic isoform p110b, but not p110a, were required for androgen-stimulated AR transactivation and cell proliferation in prostate cancer cells. Consistently, overexpression of wild-type p110b but not p110a gene led to androgen-independent AR transactivation. Silencing p110b gene in prostate cancer cells abolished tumor growth in nude mice. Of the dual (lipid and protein) kinase activities, p110b's lipid kinase activity was required for AR transactivation. Further analysis by a chromatin immunoprecipitation assay showed that p110b is indispensable for androgen-induced AR-DNA interaction. Finally, gene expression analysis of clinical specimens showed that both p85a and p110b were highly expressed in malignant prostate tissues compared to the nonmalignant compartments, and their expression levels correlated significantly with disease progression. Taken together, our data demonstrated that p85a and p110b are essential for androgen-stimulated AR transactivation, and their aberrant expression or activation might play an important role in prostate cancer progression.

show abstract

Section: Resultsmentioning

confidence: 99%

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

et al. 2008

View full text Add to dashboard Cite

show abstract

“…To provide further evidence for a critical role of PI3K signaling in the viability of HBL1 and TMD8 cells, we used the PI3K inhibitor 15e, which most potently inhibits p110α activity (IC 50 = 2 nm) but also strongly impairs other isoforms, especially p110β (IC 50 = 16 nm) (16). We found that 0.4 μM p110α inhibitor 15e blocked AKT phosphorylation in ABC DLBCL cells (Fig.…”

Section: Pi3k-pdk1 Signaling Controls Viability Of a Subset Of Abc DLmentioning

confidence: 87%

Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

Kloo

Nagel

Pfeifer

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

113

View full text Add to dashboard Cite

The activated B-cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL) represents a very aggressive human lymphoma entity. Constitutive NF-κB activation caused by chronic active B-cell receptor (BCR) signaling is common feature of many ABC DLBCL cells; however, the pathways linking BCR signaling to the NF-κB prosurvival network are largely unknown. Here we report that constitutive activity of PI3K and the downstream kinase PDK1 are essential for the viability of two ABC DLBCL cell lines that carry mutations in the BCR proximal signaling adaptor CD79B. In these cells, PI3K inhibition reduces NF-κB activity and decreases the expression of NF-κB target genes. Furthermore, PI3K and PDK1 are required for maintaining MALT1 protease activity, which promotes survival of the affected ABC DLBCL cells. These results demonstrate a critical function of PI3K-PDK1 signaling upstream of MALT1 protease and NF-κB in distinct ABC DLBCL cells and provide a rationale for the pharmacologic use of PI3K inhibitors in DLBCL therapy.

show abstract

“…With our collaborators Hayakawa et al (25)(26)(27)(28), we have previously reported the discovery of three new series of phosphatidylinositide 3-kinase inhibitors and described the detailed pharmacologic properties of a novel synthetic lead compound of the tricyclic pyridofuropyrimidine class, PI-103 (29,30). PI-103 is a potent and selective inhibitor of class I phosphatidylinositide 3-kinases, and also of mTOR and DNA-PK, which blocked the proliferation of human cancer cells in vitro and caused pharmacodynamic biomarker effects consistent with target inhibition (29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

Raynaud

Eccles

Patel

et al. 2009

Molecular Cancer Therapeutics

Self Cite

247

224

View full text Add to dashboard Cite

The phosphatidylinositide 3-kinase pathway is frequently deregulated in human cancers and inhibitors offer considerable therapeutic potential. We previously described the promising tricyclic pyridofuropyrimidine lead and chemical tool compound PI-103. We now report the properties of the pharmaceutically optimized bicyclic thienopyrimidine derivatives PI-540 and PI-620 and the resulting clinical development candidate GDC-0941. All four compounds inhibited phosphatidylinositide 3-kinase p110α with IC 50 ≤ 10 nmol/L. Despite some differences in isoform selectivity, these agents exhibited similar in vitro antiproliferative properties to PI-103 in a panel of human cancer cell lines, with submicromolar potency in PTEN-negative U87MG human glioblastoma cells and comparable phosphatidylinositide 3-kinase pathway modulation. PI-540 and PI-620 exhibited improvements in solubility and metabolism with high tissue distribution in mice. Both compounds gave improved antitumor efficacy over PI-103, following i.p. dosing in U87MG glioblastoma tumor xenografts in athymic mice, with treated/control values of 34% (66% inhibition) and 27% (73% inhibition) for PI-540 (50 mg/ kg b.i.d.) and PI-620 (25 mg/kg b.i.d.), respectively. GDC-0941 showed comparable in vitro antitumor activity to PI-103, PI-540, and PI-620 and exhibited 78% oral bioavailability in mice, with tumor exposure above 50% antiproliferative concentrations for >8 hours following 150 mg/kg p.o. and sustained phosphatidylinositide 3-kinase pathway inhibition. These properties led to excellent dose-dependent oral antitumor activity, with daily p.o. dosing at 150 mg/kg achieving 98% and 80% growth inhibition of U87MG glioblastoma and IGROV-1 ovarian cancer xenografts, respectively. Together, these data support the development of GDC-0941 as a potent, orally bioavailable inhibitor of phosphatidylinositide 3-kinase. GDC-0941 has recently entered phase I clinical trials.

show abstract

Synthesis and biological evaluation of 4-morpholino-2-phenylquinazolines and related derivatives as novel PI3 kinase p110α inhibitors

Cited by 182 publications

References 30 publications

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

Phosphoinositide 3-OH kinase p85α and p110β are essential for androgen receptor transactivation and tumor progression in prostate cancers

Critical role of PI3K signaling for NF-κB–dependent survival in a subset of activated B-cell–like diffuse large B-cell lymphoma cells

Biological properties of potent inhibitors of class I phosphatidylinositide 3-kinases: from PI-103 through PI-540, PI-620 to the oral agent GDC-0941

Contact Info

Product

Resources

About