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Discovery of (thienopyrimidin-2-yl)aminopyrimidines as potent, selective, and orally available pan-PI3-kinase and dual pan-PI3-kinase/mTOR inhibitors for the treatment of cancer.

Sutherlin DP, Sampath D, Berry M, Castanedo G, Chang Z, Chuckowree I, Dotson J, Folkes A, Friedman L, Goldsmith R, Heffron T, Lee L, Lesnick J, Lewis C, Mathieu S, Nonomiya J, Olivero A, Pang J, Prior WW, Salphati L, Sideris S, Tian Q, Tsui V, Wan NC, Wang S, Wiesmann C, Wong S, Zhu BY
J Med Chem 53 1086-97 (2010)
Related entries: 3l16, 3l17

Cited: 39 times
EuropePMC logo PMID: 20050669

Abstract

The PI3K/AKT/mTOR pathway has been shown to play an important role in cancer. Starting with compounds 1 and 2 (GDC-0941) as templates, (thienopyrimidin-2-yl)aminopyrimidines were discovered as potent inhibitors of PI3K or both PI3K and mTOR. Structural information derived from PI3K gamma-ligand cocrystal structures of 1 and 2 were used to design inhibitors that maintained potency for PI3K yet improved metabolic stability and oral bioavailability relative to 1. The addition of a single methyl group to the optimized 5 resulted in 21, which had significantly reduced potency for mTOR. The lead compounds 5 (GNE-493) and 21 (GNE-490) have good pharmacokinetic (PK) parameters, are highly selective, demonstrate knock down of pathway markers in vivo, and are efficacious in xenograft models where the PI3K pathway is deregulated. Both compounds were compared in a PI3K alpha mutated MCF7.1 xenograft model and were found to have equivalent efficacy when normalized for exposure.

Reviews - 3l13 mentioned but not cited (1)

  1. Advances in chemical proteomic evaluation of lipid kinases-DAG kinases as a case study. Ware TB, Hsu KL. Curr Opin Chem Biol 65 101-108 (2021)

Articles - 3l13 mentioned but not cited (2)



Reviews citing this publication (6)

  1. Targeting phosphoinositide 3-kinase signalling in lung cancer. Wojtalla A, Arcaro A. Crit Rev Oncol Hematol 80 278-290 (2011)
  2. Recent development of ATP-competitive small molecule phosphatidylinostitol-3-kinase inhibitors as anticancer agents. Liu Y, Wan WZ, Li Y, Zhou GL, Liu XG. Oncotarget 8 7181-7200 (2017)
  3. Therapeutic strategies of glioblastoma (GBM): The current advances in the molecular targets and bioactive small molecule compounds. Liu H, Qiu W, Sun T, Wang L, Du C, Hu Y, Liu W, Feng F, Chen Y, Sun H. Acta Pharm Sin B 12 1781-1804 (2022)
  4. Targeting PI3Kδ: emerging therapy for chronic lymphocytic leukemia and beyond. Wei M, Wang X, Song Z, Jiao M, Ding J, Meng LH, Zhang A. Med Res Rev 35 720-752 (2015)
  5. Selective and potent small-molecule inhibitors of PI3Ks. Jeong Y, Kwon D, Hong S. Future Med Chem 6 737-756 (2014)
  6. Chemical and Structural Strategies to Selectively Target mTOR Kinase. Borsari C, De Pascale M, Wymann MP. ChemMedChem 16 2744-2759 (2021)

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