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4-methylpteridinones as orally active and selective PI3K/mTOR dual inhibitors.

Liu KK, Bagrodia S, Bailey S, Cheng H, Chen H, Gao L, Greasley S, Hoffman JE, Hu Q, Johnson TO, Knighton D, Liu Z, Marx MA, Nambu MD, Ninkovic S, Pascual B, Rafidi K, Rodgers CM, Smith GL, Sun S, Wang H, Yang A, Yuan J, Zou A
Bioorg Med Chem Lett 20 6096-9 (2010)
Cited: 15 times
EuropePMC logo PMID: 20817449

Abstract

Pteridinones were designed based on a non-selective kinase template. Because of the uniqueness of the PI3K and mTOR binding pockets, a methyl group was introduced to C-4 position of the peteridinone core to give compounds with excellent selectivity for PI3K and mTOR. This series of compounds were further optimized to improve their potency against PI3Kα and mTOR. Finally, orally active compounds with improved solubility and robust in vivo efficacy in tumor growth inhibition were identified as well.

Reviews - 3oaw mentioned but not cited (2)

  1. Advanced Computational Methodologies Used in the Discovery of New Natural Anticancer Compounds. Chavda VP, Ertas YN, Walhekar V, Modh D, Doshi A, Shah N, Anand K, Chhabria M. Front Pharmacol 12 702611 (2021)
  2. 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)

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  1. A Systems Biology-Based Approach to Uncovering Molecular Mechanisms Underlying Effects of Traditional Chinese Medicine Qingdai in Chronic Myelogenous Leukemia, Involving Integration of Network Pharmacology and Molecular Docking Technology. Zhou C, Liu L, Zhuang J, Wei J, Zhang T, Gao C, Liu C, Li H, Si H, Sun C. Med Sci Monit 24 4305-4316 (2018)
  2. Analysis of the anticancer activity of curcuminoids, thiotryptophan and 4-phenoxyphenol derivatives. Parsai S, Keck R, Skrzypczak-Jankun E, Jankun J. Oncol Lett 7 17-22 (2014)
  3. Design, synthesis, and biological evaluation of tetrahydroquinolinones and tetrahydroquinolines with anticancer activity. Ryczkowska M, Maciejewska N, Olszewski M, Witkowska M, Makowiec S. Sci Rep 12 9985 (2022)


Reviews citing this publication (6)

  1. The influence of lipophilicity in drug discovery and design. Arnott JA, Planey SL. Expert Opin Drug Discov 7 863-875 (2012)
  2. 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)
  3. 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)
  4. 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)
  5. Selective and potent small-molecule inhibitors of PI3Ks. Jeong Y, Kwon D, Hong S. Future Med Chem 6 737-756 (2014)
  6. Therapeutic potential of pteridine derivatives: A comprehensive review. Carmona-Martínez V, Ruiz-Alcaraz AJ, Vera M, Guirado A, Martínez-Esparza M, García-Peñarrubia P. Med Res Rev 39 461-516 (2019)

Articles citing this publication (4)

  1. Highly Selective and Potent Thiophenes as PI3K Inhibitors with Oral Antitumor Activity. Liu KK, Zhu J, Smith GL, Yin MJ, Bailey S, Chen JH, Hu Q, Huang Q, Li C, Li QJ, Marx MA, Paderes G, Richardson PF, Sach NW, Walls M, Wells PA, Baxi S, Zou A. ACS Med Chem Lett 2 809-813 (2011)
  2. Discovery of a novel aminopyrazine series as selective PI3Kα inhibitors. Barlaam B, Cosulich S, Fitzek M, Germain H, Green S, Hanson LL, Harris CS, Hancox U, Hudson K, Lambert-van der Brempt C, Lamorlette M, Magnien F, Ouvry G, Page K, Ruston L, Ward L, Delouvrié B. Bioorg. Med. Chem. Lett. 27 3030-3035 (2017)
  3. Impact of Minor Structural Modifications on Properties of a Series of mTOR Inhibitors. Ouvry G, Clary L, Tomas L, Aurelly M, Bonnary L, Borde E, Bouix-Peter C, Chantalat L, Defoin-Platel C, Deret S, Forissier M, Harris CS, Isabet T, Lamy L, Luzy AP, Pascau J, Soulet C, Taddei A, Taquet N, Thoreau E, Varvier E, Vial E, Hennequin LF. ACS Med Chem Lett 10 1561-1567 (2019)
  4. Macrocyclization as a Source of Desired Polypharmacology. Discovery of Triple PI3K/mTOR/PIM Inhibitors. Martínez-González S, Alvarez RM, Martín JI, García AB, Riesco-Fagundo C, Varela C, Rodríguez Hergueta A, González Cantalapiedra E, Albarrán MI, Gómez-Casero E, Cebriá A, Aguirre E, Ajenjo N, Cebrián D, Di Geronimo B, Cunningham D, O'Neill M, Dave HPG, Blanco-Aparicio C, Pastor J. ACS Med Chem Lett 12 1794-1801 (2021)


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