Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent <i>in vivo</i> antitumor activity

Maira, Sauveur‐Michel; Stauffer, Frédéric; Brueggen, Josef; Furet, Pascal; Schnell, Christian; Fritsch, Christine; Brachmann, Saskia M.; Chêne, Patrick; Pover, Alain De; Schoemaker, Kevin; Fabbro, Doriano; Gabriel, Daniela; Simonen, Mika; Murphy, Leon O.; Finan, Peter M.; Sellers, William R.; García‐Echeverría, Carlos

doi:10.1158/1535-7163.mct-08-0017

Cited by 1,045 publications

(996 citation statements)

References 47 publications

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“…(55) Recently, more than 30 inhibitors for class I PI3K have been developed for the anticancer therapy. (56) Among those, orally available, minimally toxic pan-class IA PI3K inhibitors, ZSTK474, NVP-BKM120 {5-[2,6-Di(4-morpholinyl)-4-pyrimidinyl]-4-(trifluoromethyl)-2-pyridinamine}, (57) NVP-BEZ235 {2-Methyl-2-{4-[3-methyl-2-oxo-8-(quinolin-3-yl)-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl]phenyl}propanenitrile}, (58) and GDC-0941 {2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine}, (59) have already entered clinical trials in the United States. Osteoclasts are known to be crucial for bone metastasis and cancer progression in bone.…”

Section: Discussionmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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Class IA phosphatidylinositol 3-kinases (PI3Ks) are activated by growth factor receptors and regulate a wide range of cellular processes. In osteoclasts, they are activated downstream of a v b 3 integrin and colony-stimulating factor-1 receptor (c-Fms), which are involved in the regulation of bone-resorbing activity. The physiological relevance of the in vitro studies using PI3K inhibitors has been of limited value, because they inhibit all classes of PI3K. Here, we show that the osteoclast-specific deletion of the p85 genes encoding the regulatory subunit of the class IA PI3K results in an osteopetrotic phenotype caused by a defect in the bone-resorbing activity of osteoclasts. Class IA PI3K is required for the ruffled border formation and vesicular transport, but not for the formation of the sealing zone. p85a/b doubly deficient osteoclasts had a defect in macrophage colony-stimulating factor (M-CSF)-induced protein kinase B (Akt) activation and the introduction of constitutively active Akt recovered the bone-resorbing activity. Thus, the class IA PI3K-Akt pathway regulates the cellular machinery crucial for osteoclastic bone resorption, and may provide a molecular basis for therapeutic strategies against bone diseases. ß

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Section: Discussionmentioning

confidence: 99%

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Shirakawa

Nakamura

Masuda

et al. 2012

Journal of Bone and Mineral Research

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“…NVP-BEZ235 (compound 6, Figure 2) is an imidazo [4,5-c]quinoline derivative that inhibits PI3K (IC 50 ¼ 4, 76, 7, 5 and 21 nM against p110a, b, g and d) and mTOR (IC 50 ¼ 21 nM) kinase activity by binding to the ATP-binding cleft of these enzymes (Maira et al, 2008a). The compound potently inhibits proliferation in a broad panel of tumor cell lines (for example, IC 50 ¼ 10 nM, U87MG cells) by specifically blocking the biological function of PI3K signaling components (for example, IC 50 ¼ 10±1 nM, for inhibition of pSer473-Akt in U87MG cells) and inducing a G1 arrest.…”

Section: Inhibitors Of the Lipid Kinase Activity Of Pi3kmentioning

confidence: 99%

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

2008

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“…The compounds, imatinib mesylate and the dual PI3K/mTOR inhibitor NVP-BEZ235, 16 were purchased from Sequoia Research Products (Pangbourne, UK).…”

Section: In Vitro Sirna Pten Experimentsmentioning

confidence: 99%

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

et al. 2014

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Insufficiency of phosphatase and tensin homolog (PTEN) occurs in numerous tumor types and has been implicated as a resistance mechanism to receptor tyrosine kinase-targeted therapies in human cancer. In this study, we have performed a comprehensive molecular and immunohistochemical characterization of PTEN in 58 imatinib-naı¨ve and 54 imatinib-treated gastrointestinal stromal tumors (GISTs). The findings were correlated with clinicopathological data. At the genomic level, PTEN was affected mainly by mono-allelic loss, which was significantly less frequent in imatinib-naı¨ve vs imatinib-resistant tumors (9% vs 39%, Po0.001). Neither PTEN mutations nor PTEN promoter hyper-methylation were found. By immunohistochemistry, PTEN depletion was clearly related to GIST progression. Low PTEN protein expression was common (50%) and often paralleled with total immunonegativity in imatinib-resistant tumors. The abnormal PTEN protein expression correlated with PTEN loss at the genomic level (P ¼ 0.001). In addition, the effect of small interfering RNA (siRNA) PTEN knockdown on KIT signaling was examined in GIST-T1 and GIST430 cell lines, in the absence or presence of a dual PI3K/mTOR inhibitor NVP-BEZ235, alone or in combination with imatinib. In both cell lines, siRNA silencing of PTEN resulted in the substantial upregulation of PI3K-AKT and MAPK pathways. The MAPK hyperactivation was further potentiated by NVP-BEZ235 in the imatinib-sensitive GIST-T1 cells; yet, this effect was counteracted efficiently by combined treatment. In the imatinib-resistant GIST430 cells, neither NVP-BEZ235 alone or in combination with imatinib yielded sufficient inhibition of hyper-phosphorylated MAPK and downstream intermediate S6 protein. In conclusion, depleted PTEN expression associated with mono-allelic PTEN loss occurs frequently in imatinib-resistant GIST and might serve as a biomarker for stratifying patients for optimal treatment. In vitro, the PTEN insufficiency leads to hyperactivation of AKT and MAPK pathways in tumor cells. Novel therapies targeting multiple components of the integrated KIT receptor signaling pathways in imatinibresistant GIST warrant further studies.

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Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity

Cited by 1,045 publications

References 47 publications

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Class IA phosphatidylinositol 3-kinase regulates osteoclastic bone resorption through protein kinase B–mediated vesicle transport

Drug discovery approaches targeting the PI3K/Akt pathway in cancer

Frequent mono-allelic loss associated with deficient PTEN expression in imatinib-resistant gastrointestinal stromal tumors

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