AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with <i>In vitro</i> and <i>In vivo</i> Antitumor Activity

Chresta, Christine; Davies, Barry R.; Hickson, Ian; Harding, Tom; Cosulich, Sabina C.; Critchlow, Susan E.; Vincent, John P.; Ellston, Rebecca; Jones, Darren; Sini, Patrizia; James, Dominic I.; Howard, Zoe; Dudley, Phillippa; Hughes, Gareth; Smith, Lisa M.; Maguire, Sharon; Hummersone, Marc; Malagu, Karine; Menear, Keith; Jenkins, Richard O.; Jacobsen, Matt; Smith, Graeme C.M.; Guichard, Sylvie; Pass, Martin

doi:10.1158/0008-5472.can-09-1751

Cited by 702 publications

(640 citation statements)

References 36 publications

Supporting

Mentioning

600

Contrasting

Unclassified

Order By: Relevance

“…1). On the basis of these findings, AZD8055 is a better inhibitor of mTORC1 in comparison to rapamycin, consistent with another recent AZD8055 study by Chresta et al ( 7 ). In vivo studies indicate that AZD8055 can inhibit tumor growth and can even lead to tumor regression when combined with lapatinib.…”

Section: In the Spotlightsupporting

confidence: 88%

mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop

Keniry

Parsons

2011

Cancer Discovery

View full text Add to dashboard Cite

Summary: mTOR inhibition with the ATP-competitive kinase inhibitor AZD8055 induces receptor tyrosine kinasedependent feedback activation of AKT. Cancer Discovery; 1(3); 203-4. ©2011 AACR. IN THE SPOTLIGHTand deforolimus-employ an allosteric mechanism to block mTORC1 output ( 6 ). In contrast, second generation mTOR inhibitors such as AZD8055, Torin1, PP242, and PP30 competitively target the ATP binding site to impede kinase activity of both TORC1 and TORC2 ( 6 ). In addition to these drugs, dual ATP-binding kinase inhibitors of mTOR and phosphoinositide 3-kinase (PI3K; NVP-BEZ253 and PI-103) may prove more efficacious by inhibiting oncogenic signaling events to a greater extent ( 6 ). In this issue of Cancer Discovery , Rodrik-Outmezguine and colleagues ( 1 ) show a side-by-side comparison of mTORC inhibition with rapamycin and AZD8055, which revealed surprising changes in mTOR signaling. Rapamycin treatment led to an almost complete loss in the mTORC1 phosphorylation of p70S6K (Thr389) with essentially no impact on the phosphorylation of 4EBP1 (Thr65 and Thr70), whereas phospho AKT (Ser473) was increased. In contrast, AZD8055 treatment led to strong reductions in phospho 70S6K (Thr389), phospho 4EBP1 (Thr37/40, Thr65, and Thr70) and phospho AKT (Ser473; ref. 1). On the basis of these findings, AZD8055 is a better inhibitor of mTORC1 in comparison to rapamycin, consistent with another recent AZD8055 study by Chresta et al. ( 7 ). In vivo studies indicate that AZD8055 can inhibit tumor growth and can even lead to tumor regression when combined with lapatinib. Therefore, AZD8055 shows promise as a therapeutic agent, but harnessing the full potential will require a greater understanding of the web of feedback loops that intertwine PI3K, mTOR, and RTKs.An astonishing result from Rodrik-Outmezguine and colleagues ( 1 ) is the rebound in AKT activity in the absence of mTORC2. Scores of studies use levels of phopho AKT (Ser473) as a barometer of AKT activity. Yet, in this study AKT output is high after 8 hours of AZD8055 treatment, even though phospho AKT (Ser473) is low. The logic follows that AKT output and phospho AKT (Ser 473) may be discordant in other instances. Conceivably, phospho AKT (Thr308), which is modified on a key T-loop residue, is a more reliable indicator of AKT activity. AKT phosphorylation on Thr308 is essentially required for kinase activity ( 8 ). Phosphorylation on Thr308 increases AKT kinase activity by at least 100-fold, whereas phosphorylation on Ser473 mediates stabilization of the active conformation of the kinase, increasing activity by roughly another 10-fold ( 9 ). The gain in AKT output in the absence of Ser473 phosphorylation suggests that the active conformation of AKT may be stabilized in another manner, perhaps by interacting with the hydrophobic motif of another protein.In this issue of Cancer Discovery , Rodrik-Outmezguine and colleagues ( 1 ) discover a surprising biphasic regulation of AKT after inhibition of mTOR kinase complexes TORC1 and TORC2. This novel feedback mechanism wa...

show abstract

Section: In the Spotlightsupporting

confidence: 88%

mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop

Keniry

Parsons

2011

Cancer Discovery

View full text Add to dashboard Cite

show abstract

“…Chemical inhibitors, including BMS-777607, AZD8055, AZD1152, XAV939, GDC-0449, SB216763, wortmannin, PD98059, RAD001, and PP242, were from Selleck Chemicals. Chemical structures of BMS-7776-7 and AZD8055 have been previously published (16,22). Doxorubicin, cisplatin, gemcitabine, methotrexate, and 5-fluorouracil were from Fisher Scientific.…”

Section: Cell Lines Antibodies Inhibitors and Chemoagentsmentioning

confidence: 99%

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Zeng

Sharma

Zhou

et al. 2014

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Tyrosine kinase inhibitor BMS-777067 is an inhibitor of RON/MET receptor tyrosine kinases currently under clinical trials. Here, we report the synergistic activity of BMS-777607 in combination with mTOR inhibitor AZD8055 in killing chemoresistant pancreatic cancer and cancer stem cells. Treatment of pancreatic cancer L3.6pl cells with BMS-777607 alone inhibited clonogenic growth and moderately induced apoptotic death. However, BMS-777607 caused extensive polyploidy in L3.6pl cells through inhibition of aurora kinase B activity, independent of RON expression. In contrast, L3.6pl-derived cancer stem cells were highly resistant to BMS-777607-induced growth inhibition and apoptosis. The effect of BMS-777607 on induction of cancer stem cell polyploidy was also weak. BMS-777607-induced polyploidy features a predominant cell population with 8N chromosome content in both L3.6pl and cancer stem cells. These cells also showed decreased sensitivity toward chemotherapeutics by increased survival of IC 50 values in response to doxorubicin, cisplatin, methotrexate, 5-fluorouracial, and gemcitabine. Among a panel of chemical inhibitors that target different signaling proteins, we found that BMS-777607 in combination with mTOR inhibitor AZD8055 exerted synergistic effects on L3.6pl and cancer stem cells. More than 70% of L3.6pl and cancer stem cells lost their viability when both inhibitors were used. Specifically, BMS-777607 in combination with inhibition of mTORC2, but not mTORC1, was responsible for the observed synergism. Our findings demonstrate that BMS-777607 at therapeutic doses exerts inhibitory activities on pancreatic cancer cells but also induces polyploidy insensitive to chemotherapeutics. Combination of BMS-777607 with AZD8055 achieves the maximal cytotoxic effect on pancreatic cancer and cancer stem cells. Mol Cancer Ther; 13(1); 37-48. Ó2013 AACR.

show abstract

“…Consequently, intense efforts are now underway to develop inhibitors of the PI3K/AKT/mTOR pathway, including ATP-competitive small molecule mTOR kinase inhibitors targeting both mTORC1 and mTORC2 (20). Several recent reports have described biochemical and cellular properties of selective ATP-competitive inhibitors of mTORC1 and mTORC2 (21)(22)(23)(24)(25)(26). These chemically distinct compounds all show suppression of both mTORC1-and mTORC2-mediated downstream signaling in various tumor cell lines.…”

mentioning

confidence: 99%

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

Bhagwat

Gokhale

Crew

et al. 2011

Molecular Cancer Therapeutics

171

142

View full text Add to dashboard Cite

The phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway is frequently activated in human cancers, and mTOR is a clinically validated target. mTOR forms two distinct multiprotein complexes, mTORC1 and mTORC2, which regulate cell growth, metabolism, proliferation, and survival. Rapamycin and its analogues partially inhibit mTOR through allosteric binding to mTORC1, but not mTORC2, and have shown clinical utility in certain cancers. Here, we report the preclinical characterization of OSI-027, a selective and potent dual inhibitor of mTORC1 and mTORC2 with biochemical IC 50 values of 22 nmol/L and 65 nmol/L, respectively. OSI-027 shows more than 100-fold selectivity for mTOR relative to PI3Ka, PI3Kb, PI3Kg, and DNA-PK. OSI-027 inhibits phosphorylation of the mTORC1 substrates 4E-BP1 and S6K1 as well as the mTORC2 substrate AKT in diverse cancer models in vitro and in vivo. OSI-027 and OXA-01 (close analogue of OSI-027) potently inhibit proliferation of several rapamycin-sensitive and -insensitive nonengineered and engineered cancer cell lines and also, induce cell death in tumor cell lines with activated PI3K-AKT signaling.

show abstract

AZD8055 Is a Potent, Selective, and Orally Bioavailable ATP-Competitive Mammalian Target of Rapamycin Kinase Inhibitor with In vitro and In vivo Antitumor Activity

Cited by 702 publications

References 36 publications

mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop

mTOR Inhibition, the Second Generation: ATP-Competitive mTOR Inhibitor Initiates Unexpected Receptor Tyrosine Kinase–Driven Feedback Loop

Synergistic Activities of MET/RON Inhibitor BMS-777607 and mTOR Inhibitor AZD8055 to Polyploid Cells Derived from Pancreatic Cancer and Cancer Stem Cells

Preclinical Characterization of OSI-027, a Potent and Selective Inhibitor of mTORC1 and mTORC2: Distinct from Rapamycin

Contact Info

Product

Resources

About