Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors

Mortensen, Deborah S.; Perrin-Ninkovic, Sophie; Harris, Roy; Lee, Branden G.S.; Shevlin, Graziella; Hickman, Matt; Khambatta, Gody; Bisonette, Rene R.; Fultz, Kimberly E.; Sankar, Sabita

doi:10.1016/j.bmcl.2011.09.035

Cited by 33 publications

(35 citation statements)

References 22 publications

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“…CC-223 is a potent and selective inhibitor of mTOR kinase CC-223 was identified following compound optimization effort that began with an imidazo [4,5-b]pyrazin-2-one screening hit (15). Optimization for potency, selectivity and PK properties led to the dihydropyrazino[2,3-b]pyrazin-2(1H)-one series and the discovery of CC-223 (Fig.…”

Section: Resultsmentioning

confidence: 99%

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

Mortensen¹,

Fultz²,

Xu³

et al. 2015

Molecular Cancer Therapeutics

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Section: Resultsmentioning

confidence: 99%

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

Mortensen¹,

Fultz²,

Xu³

et al. 2015

Molecular Cancer Therapeutics

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“…CC214-1 and CC214-2 were provided by Celgene Corporation (San Diego, U.S.A.). The development of the series that led to CC214 compounds (12) and its structure (10) have been described. P-Akt Ser473, P-Akt Thr308, P-NDRG1 Thr346, P-S6 Ser235/236, S6, cleaved PARP, P-4E-BP1 Thr37-46, 4E-BP1, eIF4E, LC3B, Atg-5, Atg-5/12 antibodies were purchased from Cell Signaling Technologies.…”

Section: Methodsmentioning

confidence: 99%

The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Gini

Zanca

Guo

et al. 2013

Clinical Cancer Research

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Purpose mTOR pathway hyperactivation occurs in nearly 90% of glioblastomas, but the allosteric mTOR inhibitor rapamycin has failed in the clinic. Here we examine the efficacy of the newly discovered ATP-competitive mTOR kinase inhibitors CC214-1 and CC214-2 in glioblastoma, identifying molecular determinants of response and mechanisms of resistance, and develop a pharmacological strategy to overcome it. Experimental design We performed in vitro and in vivo studies in glioblastoma cell lines and an intracranial model to: determine the potential efficacy of the recently reported mTOR kinase inhibitors CC214-1 (in vitro use) and CC214-2 (in vivo use) at inhibiting rapamycin resistant signaling and blocking GBM growth and a novel single cell technology, DNA Encoded Antibody Libraries, was used to identify mechanisms of resistance. Results Here we demonstrate that CC214-1 and CC214-2 suppress rapamycin-resistant mTORC1 signaling; block mTORC2 signaling and significantly inhibit the growth of glioblastomas in vitro and in vivo. EGFRvIII expression and PTEN loss enhance sensitivity to CC214 compounds, consistent with enhanced efficacy in strongly mTOR-activated tumors. Importantly, CC214 compounds potently induce autophagy, preventing tumor cell death. Genetic or pharmacologic inhibition of autophagy greatly sensitizes GBM cells and orthotopic xenografts to CC214-1 and CC214-2 induced cell death. Conclusions These results identify CC214-1 and CC214-2 as potentially efficacious mTOR kinase inhibitors in GBM and suggest a strategy for identifying patients most likely to benefit from mTOR inhibition. This study also demonstrates a central role for autophagy in preventing mTOR-kinase inhibitor-mediated tumor cell death, and suggests a pharmacological strategy for overcoming it.

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“…In 2011, Mortensen et al [84] reported the discovery of the imidazo [4, 5-b] pyrazin-2-one series (247) as selective mTOR kinase inhibitors (e.g., 248 and 249). As the continued studies, through ring-expansion of the imidazo-ring by insertion of a methylene unit, they [85] discovered a new series of potent and selective mTOR kinase inhibitors (250) with exquisite kinase selectivity (mTOR IC 50 ~ 2-176 nM, PI3Kα IC 50 > = 526 nM), which led to the identification of CC214-2 (251, mTOR IC 50 =0.002 nM, PI3Kα IC 50 =1.38 nM), an orally available mTOR kinase inhibitor with demonstrated anti-tumor activity in mice.…”

Section: Pyridines Quinolines Indoles and Indazolesmentioning

confidence: 99%

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

Liu

Wan

et al. 2016

Oncotarget

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Discovery and SAR exploration of a novel series of imidazo[4,5-b]pyrazin-2-ones as potent and selective mTOR kinase inhibitors

Cited by 33 publications

References 22 publications

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

CC-223, a Potent and Selective Inhibitor of mTOR Kinase: In Vitro and In Vivo Characterization

The mTOR Kinase Inhibitors, CC214-1 and CC214-2, Preferentially Block the Growth of EGFRvIII-Activated Glioblastomas

Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents

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