Literature DB >> 29541370

Discovery of Pyridopyrimidinones as Potent and Orally Active Dual Inhibitors of PI3K/mTOR.

Tao Yu1, Ning Li1, Chengde Wu1, Amy Guan1, Yi Li1, Zhengang Peng1, Miao He1, Jie Li1, Zhen Gong1, Lei Huang1, Bo Gao1, Dongling Hao1, Jikui Sun1, Yan Pan1, Liang Shen1, Chichung Chan1, Xiulian Lu2, Hongyu Yuan2, Yongguo Li2, Jian Li1, Shuhui Chen1.   

Abstract

The identification and lead optimization of a series of pyridopyrimidinone derivatives are described as a novel class of efficacious dual PI3K/mTOR inhibitors, resulting in the discovery of 31. Compound 31 exhibited high enzyme activity against PI3K and mTOR, potent suppression of Akt and p70s6k phosphorylation in cell assays, and good pharmacokinetic profile. Furthermore, compound 31 demonstrated in vivo efficacy in a PC-3M tumor xenograft model.

Entities:  

Year:  2018        PMID： 29541370      PMCID： PMC5846042          DOI： 10.1021/acsmedchemlett.8b00002

Source DB:  PubMed          Journal:  ACS Med Chem Lett        ISSN： 1948-5875            Impact factor:   4.345


  17 in total

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Journal:  J Med Chem       Date:  2011-10-07       Impact factor: 7.446

5.  A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.

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Journal:  Cancer Cell       Date:  2006-05       Impact factor: 31.743

6.  PKI-179: an orally efficacious dual phosphatidylinositol-3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitor.

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7.  Bis(morpholino-1,3,5-triazine) derivatives: potent adenosine 5'-triphosphate competitive phosphatidylinositol-3-kinase/mammalian target of rapamycin inhibitors: discovery of compound 26 (PKI-587), a highly efficacious dual inhibitor.

Authors:  Aranapakam M Venkatesan; Christoph M Dehnhardt; Efren Delos Santos; Zecheng Chen; Osvaldo Dos Santos; Semiramis Ayral-Kaloustian; Gulnaz Khafizova; Natasja Brooijmans; Robert Mallon; Irwin Hollander; Larry Feldberg; Judy Lucas; Ker Yu; James Gibbons; Robert T Abraham; Inder Chaudhary; Tarek S Mansour
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8.  Lead optimization of N-3-substituted 7-morpholinotriazolopyrimidines as dual phosphoinositide 3-kinase/mammalian target of rapamycin inhibitors: discovery of PKI-402.

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Journal:  J Med Chem       Date:  2010-01-28       Impact factor: 7.446

Review 9.  Targeting PI3K signalling in cancer: opportunities, challenges and limitations.

Authors:  Jeffrey A Engelman
Journal:  Nat Rev Cancer       Date:  2009-08       Impact factor: 60.716

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Journal:  Mol Cancer Ther       Date:  2008-07-07       Impact factor: 6.261
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Review 3.  KYNA Derivatives with Modified Skeleton; Hydroxyquinolines with Potential Neuroprotective Effect.

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