3ibe › Citations

ATP-competitive inhibitors of the mammalian target of rapamycin: design and synthesis of highly potent and selective pyrazolopyrimidines.

Zask A, Verheijen JC, Curran K, Kaplan J, Richard DJ, Nowak P, Malwitz DJ, Brooijmans N, Bard J, Svenson K, Lucas J, Toral-Barza L, Zhang WG, Hollander I, Gibbons JJ, Abraham RT, Ayral-Kaloustian S, Mansour TS, Yu K
J Med Chem 52 5013-6 (2009)
Cited: 39 times
EuropePMC logo PMID: 19645448

Abstract

The mammalian target of rapamycin (mTOR), a central regulator of growth, survival, and metabolism, is a validated target for cancer therapy. Rapamycin and its analogues, allosteric inhibitors of mTOR, only partially inhibit one mTOR protein complex. ATP-competitive, global inhibitors of mTOR that have the potential for enhanced anticancer efficacy are described. Structural features leading to potency and selectivity were identified and refined leading to compounds with in vivo efficacy in tumor xenograft models.

Reviews - 3ibe 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 - 3ibe mentioned but not cited (4)

  1. Docking studies on isoform-specific inhibition of phosphoinositide-3-kinases. Sabbah DA, Vennerstrom JL, Zhong H. J Chem Inf Model 50 1887-1898 (2010)
  2. Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents. Llorach-Pares L, Nonell-Canals A, Sanchez-Martinez M, Avila C. Mar Drugs 15 E366 (2017)
  3. Thiazolidinedione-based PI3Kα inhibitors: an analysis of biochemical and virtual screening methods. Pinson JA, Schmidt-Kittler O, Zhu J, Jennings IG, Kinzler KW, Vogelstein B, Chalmers DK, Thompson PE. ChemMedChem 6 514-522 (2011)
  4. Modeling of RAS complexes supports roles in cancer for less studied partners. Engin HB, Carlin D, Pratt D, Carter H. BMC Biophys 10 5 (2017)


Reviews citing this publication (9)

  1. mTOR inhibitors in cancer therapy. Zaytseva YY, Valentino JD, Gulhati P, Evers BM. Cancer Lett 319 1-7 (2012)
  2. Therapeutic targeting of the mTOR-signalling pathway in cancer: benefits and limitations. Moschetta M, Reale A, Marasco C, Vacca A, Carratù MR. Br J Pharmacol 171 3801-3813 (2014)
  3. Allosteric and ATP-competitive kinase inhibitors of mTOR for cancer treatment. García-Echeverría C. Bioorg Med Chem Lett 20 4308-4312 (2010)
  4. Furthering the design and the discovery of small molecule ATP-competitive mTOR inhibitors as an effective cancer treatment. Lv X, Ma X, Hu Y. Expert Opin Drug Discov 8 991-1012 (2013)
  5. 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)
  6. Recent advances in the discovery of small-molecule ATP competitive mTOR inhibitors: a patent review. Zask A, Verheijen JC, Richard DJ. Expert Opin Ther Pat 21 1109-1127 (2011)
  7. mTOR Inhibition Role in Cellular Mechanisms. Zaza G, Granata S, Caletti C, Signorini L, Stallone G, Lupo A. Transplantation 102 S3-S16 (2018)
  8. Chemical and Structural Strategies to Selectively Target mTOR Kinase. Borsari C, De Pascale M, Wymann MP. ChemMedChem 16 2744-2759 (2021)
  9. Insights into the medicinal chemistry of heterocycles integrated with a pyrazolo[1,5-a]pyrimidine scaffold. Hammouda MM, Gaffer HE, Elattar KM. RSC Med Chem 13 1150-1196 (2022)

Articles citing this publication (25)

  1. Myc proteins as therapeutic targets. Gustafson WC, Weiss WA. Oncogene 29 1249-1259 (2010)
  2. 5-(4,6-Dimorpholino-1,3,5-triazin-2-yl)-4-(trifluoromethyl)pyridin-2-amine (PQR309), a Potent, Brain-Penetrant, Orally Bioavailable, Pan-Class I PI3K/mTOR Inhibitor as Clinical Candidate in Oncology. Beaufils F, Cmiljanovic N, Cmiljanovic V, Bohnacker T, Melone A, Marone R, Jackson E, Zhang X, Sele A, Borsari C, Mestan J, Hebeisen P, Hillmann P, Giese B, Zvelebil M, Fabbro D, Williams RL, Rageot D, Wymann MP. J Med Chem 60 7524-7538 (2017)
  3. The susceptibility of trypanosomatid pathogens to PI3/mTOR kinase inhibitors affords a new opportunity for drug repurposing. Diaz-Gonzalez R, Kuhlmann FM, Galan-Rodriguez C, Madeira da Silva L, Saldivia M, Karver CE, Rodriguez A, Beverley SM, Navarro M, Pollastri MP. PLoS Negl Trop Dis 5 e1297 (2011)
  4. The role of mTOR signaling in controlling mammalian life span: what a fungicide teaches us about longevity. Sharp ZD, Strong R. J Gerontol A Biol Sci Med Sci 65 580-589 (2010)
  5. Pyrazolo[4,3-d]pyrimidine bioisostere of roscovitine: evaluation of a novel selective inhibitor of cyclin-dependent kinases with antiproliferative activity. Jorda R, Havlícek L, McNae IW, Walkinshaw MD, Voller J, Sturc A, Navrátilová J, Kuzma M, Mistrík M, Bártek J, Strnad M, Krystof V. J Med Chem 54 2980-2993 (2011)
  6. Identification of pyrimidine derivatives as hSMG-1 inhibitors. Gopalsamy A, Bennett EM, Shi M, Zhang WG, Bard J, Yu K. Bioorg Med Chem Lett 22 6636-6641 (2012)
  7. Pyrazolopyrimidines as highly potent and selective, ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR): optimization of the 1-substituent. Curran KJ, Verheijen JC, Kaplan J, Richard DJ, Toral-Barza L, Hollander I, Lucas J, Ayral-Kaloustian S, Yu K, Zask A. Bioorg Med Chem Lett 20 1440-1444 (2010)
  8. Incorporation of water-solubilizing groups in pyrazolopyrimidine mTOR inhibitors: discovery of highly potent and selective analogs with improved human microsomal stability. Richard DJ, Verheijen JC, Curran K, Kaplan J, Toral-Barza L, Hollander I, Lucas J, Yu K, Zask A. Bioorg Med Chem Lett 19 6830-6835 (2009)
  9. Predicting mTOR inhibitors with a classifier using recursive partitioning and Naïve Bayesian approaches. Wang L, Chen L, Liu Z, Zheng M, Gu Q, Xu J. PLoS One 9 e95221 (2014)
  10. Discovery of 2-arylthieno[3,2-d]pyrimidines containing 8-oxa-3-azabi-cyclo[3.2.1]octane in the 4-position as potent inhibitors of mTOR with selectivity over PI3K. Verheijen JC, Yu K, Toral-Barza L, Hollander I, Zask A. Bioorg Med Chem Lett 20 375-379 (2010)
  11. 6-Aryl substituted 4-(4-cyanomethyl) phenylamino quinazolines as a new class of isoform-selective PI3K-alpha inhibitors. Yadav RR, Guru SK, Joshi P, Mahajan G, Mintoo MJ, Kumar V, Bharate SS, Mondhe DM, Vishwakarma RA, Bhushan S, Bharate SB. Eur J Med Chem 122 731-743 (2016)
  12. Synthesis of 5-substituted-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one analogs and their biological evaluation as anticancer agents: mTOR inhibitors. Reddy GL, Guru SK, Srinivas M, Pathania AS, Mahajan P, Nargotra A, Bhushan S, Vishwakarma RA, Sawant SD. Eur J Med Chem 80 201-208 (2014)
  13. Identification of small molecule enzyme inhibitors as broad-spectrum anthelmintics. Tyagi R, Elfawal MA, Wildman SA, Helander J, Bulman CA, Sakanari J, Rosa BA, Brindley PJ, Janetka JW, Aroian RV, Mitreva M. Sci Rep 9 9085 (2019)
  14. Novel purine and pyrazolo[3,4-d]pyrimidine inhibitors of PI3 kinase-alpha: Hit to lead studies. Gilbert AM, Nowak P, Brooijmans N, Bursavich MG, Dehnhardt C, Santos ED, Feldberg LR, Hollander I, Kim S, Lombardi S, Park K, Venkatesan AM, Mallon R. Bioorg Med Chem Lett 20 636-639 (2010)
  15. Discovery of 3,6-dihydro-2H-pyran as a morpholine replacement in 6-aryl-1H-pyrazolo[3,4-d]pyrimidines and 2-arylthieno[3,2-d]pyrimidines: ATP-competitive inhibitors of the mammalian target of rapamycin (mTOR). Kaplan J, Verheijen JC, Brooijmans N, Toral-Barza L, Hollander I, Yu K, Zask A. Bioorg Med Chem Lett 20 640-643 (2010)
  16. Ligand-based 3-D pharmacophore generation and molecular docking of mTOR kinase inhibitors. Tanneeru K, Guruprasad L. J Mol Model 18 1611-1624 (2012)
  17. Design, synthesis, and biological evaluation of imidazo[1,2-b]pyridazine derivatives as mTOR inhibitors. Mao B, Gao S, Weng Y, Zhang L, Zhang L. Eur J Med Chem 129 135-150 (2017)
  18. A selectivity study on mTOR/PI3Kα inhibitors by homology modeling and 3D-QSAR. Ran T, Lu T, Yuan H, Liu H, Wang J, Zhang W, Leng Y, Lin G, Zhuang S, Chen Y. J Mol Model 18 171-186 (2012)
  19. An in silico protocol for identifying mTOR inhibitors from natural products. Chen L, Wang L, Gu Q, Xu J. Mol Divers 18 841-852 (2014)
  20. Novel imidazolopyrimidines as dual PI3-Kinase/mTOR inhibitors. Venkatesan AM, Dehnhardt CM, Chen Z, Santos ED, Dos Santos O, Bursavich M, Gilbert AM, Ellingboe JW, Ayral-Kaloustian S, Khafizova G, Brooijmans N, Mallon R, Hollander I, Feldberg L, Lucas J, Yu K, Gibbons J, Abraham R, Mansour TS. Bioorg Med Chem Lett 20 653-656 (2010)
  21. Conformational selection versus induced fit in kinases: the case of PI3K-γ. D'Abramo M, Rabal O, Oyarzabal J, Gervasio FL. Angew Chem Int Ed Engl 51 642-646 (2012)
  22. Synthesis and Biological Evaluation of N- Pyrazolyl Derivatives and Pyrazolopyrimidine Bearing a Biologically Active Sulfonamide Moiety as Potential Antimicrobial Agent. Hafez HN, El-Gazzar AR. Molecules 21 E1156 (2016)
  23. A facile, regioselective synthesis of novel 3-(N-phenylcarboxamide)pyrazolo[1,5-a]pyrimidine analogs in the presence of KHSO4 in aqueous media assisted by ultrasound and their antibacterial activities. Kaping S, Boiss I, Singha LI, Helissey P, Vishwakarma JN. Mol Divers 20 379-390 (2016)
  24. 18F-labeled pyrazolo[1,5-a]pyrimidine derivatives: synthesis from 2,4-dinitrobenzamide and tosylate precursors and comparative biological evaluation for tumor imaging with positron emission tomography. Xu J, Liu H, Li G, He Y, Ding R, Wang X, Feng M, Zhang S, Chen Y, Li S, Zhao M, Li Y, Qi C, Dang Y. Molecules 17 3774-3793 (2012)
  25. Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu7 Receptor Modulation Activity and Antipsychotic-Like Properties. Kaczorowska K, Stankiewicz A, Bugno R, Paluchowska MH, Burnat G, Brański P, Cieślik P, Wierońska JM, Milik M, Nowak M, Przybyłowicz A, Kozioł A, Hogendorf A, Hogendorf AS, Kalinowska-Tłuścik J, Duszyńska B, Pilc A, Bojarski AJ. Int J Mol Sci 24 1981 (2023)


Quick links