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Identification of a Potent Phosphoinositide 3‐Kinase Pan Inhibitor Displaying a Strategic Carboxylic Acid Group and Development of Its Prodrugs
Author(s) -
Pirali Tracey,
Ciraolo Elisa,
Aprile Silvio,
Massarotti Alberto,
Berndt Alex,
Griglio Alessia,
Serafini Marta,
Mercalli Valentina,
Landoni Clarissa,
Campa Carlo Cosimo,
Margaria Jean Piero,
Silva Rangel L.,
Grosa Giorgio,
Sorba Giovanni,
Williams Roger,
Hirsch Emilio,
Tron Gian Cesare
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700340
Subject(s) - pi3k/akt/mtor pathway , prodrug , phosphoinositide 3 kinase , kinase , toxicity , pharmacology , gene isoform , medicine , signal transduction , chemistry , computational biology , biology , biochemistry , gene
Activation of the phosphoinositide 3‐kinase (PI3K) pathway is a key signaling event in cancer, inflammation, and other proliferative diseases. PI3K inhibitors are already approved for some specific clinical indications, but their systemic on‐target toxicity limits their larger use. In particular, whereas toxicity is tolerable in acute treatment of life‐threatening diseases, this is less acceptable in chronic conditions. In the past, the strategy to overcome this drawback was to block selected isoforms mainly expressed in leukocytes, but redundancy within the PI3K family members challenges the effectiveness of this approach. On the other hand, decreasing exposure to selected target cells represents a so‐far unexplored alternative to circumvent systemic toxicity. In this manuscript, we describe the generation of a library of triazolylquinolones and the development of the first prodrug pan‐PI3K inhibitor.