Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers

Barlaam, Bernard; Cosulich, Sabina; Delouvrié, Bénédicte; Ellston, Rebecca; Fitzek, Martina; Germain, Hervé; Green, Stephen; Hancox, Urs J.; Harris, Craig S.; Hudson, Kevin; Brempt, Christine Lambert‐van der; Lebraud, Honorine; Magnien, Françoise; Lamorlette, Maryannick; Griffon, Antoine Le; Morgentin, Rémy; Ouvry, Gilles; Page, Ken; Pasquet, Georges; Polanska, Urszula M.; Ruston, Linette; Saleh, Twana; Vautier, Michel; Ward, Lara

doi:10.1016/j.bmcl.2015.10.002

Cited by 33 publications

(26 citation statements)

References 27 publications

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“…In the study, the validity of 18 F-FDG uptake as a surrogate marker was supported by other PD marker data where cancer cell proliferation measured by Ki67 expression also favoured the same optimum biological dose of the 18 F-FDG PET data. Consistent with the study by Cejka et al , we too show that the 18 F-FDG PET changes seen at 12.5, 25 and 50mg/kg are linked closely to the anti-tumour activity of AZD8835 shown in the efficacy growth curve in the paper by Barlaam et al [ 7 ].…”

Section: Discussionsupporting

confidence: 93%

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The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor

et al. 2017

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BackgroundThe phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development. It has been used widely with PI3K inhibitors both clinically and pre-clinically because of the role of the PI3K pathway in glucose metabolism. In this study we investigated the potential of 18F-FDG PET as a non-invasive pharmacodynamic biomarker for AZD8835. We sought to understand if 18F-FDG PET could determine the minimally effective dose of AZD8835 and correlate with other pharmacodynamic biomarkers for validation of its use in clinical development. 18F-FDG PET scans were performed in nude mice in the BT474C breast xenograft model. Mice were fasted prior to imaging and static 18F-FDG PET was performed. Treatment groups received AZD8835 by oral gavage at a dose volume of 10ml/kg. Treatment groups received either 3, 6, 12.5, 25 or 50mg/kg AZD8835. Tumour growth was monitored throughout the study, and at the end of the imaging procedure, tumours were taken and a full pharmacodynamic analysis was performed.ResultsResults showed that AZD8835 reduced 18F-FDG uptake at a dose of 12.5, 25 and 50mg/kg with no significant reduction at doses of 3 and 6mg/kg. These results were consistent with other pharmacodynamics biomarkers measured and show 18F-FDG PET as a sensitive biomarker with the ability to determine the minimal effective dose of AZD8835.ConclusionsOur pre-clinical studies support the use of 18F-FDG PET imaging as a sensitive and non- invasive pharmacodynamic biomarker (understanding the role of PI3K signalling in glucose uptake) for AZD8835 with a decrease in 18F-FDG uptake observed at only two hours post treatment. The decrease in 18F-FDG uptake was dose dependent and data showed excellent PK/PD correlation. This data supports and parallels observations obtained with this class of compounds in patients

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Section: Discussionsupporting

confidence: 93%

“…AZD8835 (AstraZeneca) is a further example of a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. It selectively inhibits wild type and mutant forms of PI3Kα with equivalent potency and induces apoptosis and growth inhibition in mutant PIK3CA tumour models [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor

et al. 2017

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“…Cellular assays measuring inhibitory activity of AZD8835 against each of the Class I PI3K isoforms demonstrated rank order sensitivity consistent with the data from isolated enzyme assays (Table 1). Additional selectivity profiling confirmed the broader kinase selectivity of AZD8835 (19).…”

Section: Azd8835 Selectively Inhibits Pi3ka and Pi3kdmentioning

confidence: 64%

“…Profiling of AZD8835 in in vitro enzyme and cellular assays See elsewhere for details (19). Inhibition of recombinant PI3Ka, PI3Kb, PI3Kd, and PI3Kg was evaluated in ADP Kinase Glo-based enzyme assays at AZ.…”

Section: Compounds and Formulationmentioning

confidence: 99%

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Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

Hudson

Hancox

Trigwell

et al. 2016

Molecular Cancer Therapeutics

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The PIK3CA gene, encoding the p110a catalytic unit of PI3Ka, is one of the most frequently mutated oncogenes in human cancer. Hence, PI3Ka is a target subject to intensive efforts in identifying inhibitors and evaluating their therapeutic potential. Here, we report studies with a novel PI3K inhibitor, AZD8835, currently in phase I clinical evaluation. AZD8835 is a potent inhibitor of PI3Ka and PI3Kd with selectivity versus PI3Kb, PI3Kg, and other kinases that preferentially inhibited growth in cells with mutant PIK3CA status, such as in estrogen receptor-positive (ER þ ) breast cancer cell lines BT474, MCF7, and T47D (submmol/L GI 50 s). Consistent with this, AZD8835 demonstrated antitumor efficacy in corresponding breast cancer xenograft models when dosed continuously. In addition, an alternative approach of intermittent high-dose scheduling (IHDS) was explored given our observations that higher exposures achieved greater pathway inhibition and induced apoptosis. Indeed, using IHDS, monotherapy AZD8835 was able to induce tumor xenograft regression. Furthermore, AZD8835 IHDS in combination with other targeted therapeutic agents further enhanced antitumor activity (up to 92% regression). Combination partners were prioritized on the basis of our mechanistic insights demonstrating signaling pathway cross-talk, with a focus on targeting interdependent ER and/or CDK4/6 pathways or alternatively a node (mTOR) in the PI3K-pathway, approaches with demonstrated clinical benefit in ER þ breast cancer patients. In summary, AZD8835 IHDS delivers strong antitumor efficacy in a range of combination settings and provides a promising alternative to continuous dosing to optimize the therapeutic index in patients. Such schedules merit clinical evaluation. Mol Cancer Ther; 15(5); 877-89. Ó2016 AACR.

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A Perspective Study on the RTK, PI3K, B‐Raf, CDK and the Multi‐Protein Targeting in Medicinal Chemistry

Mohamed

Kerdawy

2022

Chemistry & Biodiversity

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The cellular signaling pathway components that control the different stages of cell maturation such as RTK, PI3K, B-Raf, and CDK represent crucial antitumor drug targets. The isoform diversity of these components revealed multi-divergent vents for cancer cells to develop several resistance mechanisms against these new selective drug targets. This review article illustrates the complex nature of cancer, moreover, molecular tracing of tumor resistance towards certain signaling pathways was presented. Several crucial interventions in this regard for antitumor agents' development were pointed out. The antitumor activities of several cancer chemotherapies targeting kinases were also discussed with a special focus on the structural bases for the design of protein kinase inhibitors. Additionally, a focused literature survey about the various targeted multi-kinase inhibition approaches as a mean to overcome cancer resistance was also included.

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Discovery of 1-(4-(5-(5-amino-6-(5-tert-butyl-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)-1-ethyl-1,2,4-triazol-3-yl)piperidin-1-yl)-3-hydroxypropan-1-one (AZD8835): A potent and selective inhibitor of PI3Kα and PI3Kδ for the treatment of cancers

Cited by 33 publications

References 27 publications

The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor

The use of 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) as a non-invasive pharmacodynamic biomarker to determine the minimally pharmacologically active dose of AZD8835, a novel PI3Kα inhibitor

Intermittent High-Dose Scheduling of AZD8835, a Novel Selective Inhibitor of PI3Kα and PI3Kδ, Demonstrates Treatment Strategies forPIK3CA-Dependent Breast Cancers

A Perspective Study on the RTK, PI3K, B‐Raf, CDK and the Multi‐Protein Targeting in Medicinal Chemistry

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