Potent dual inhibitors of TORC1 and TORC2 complexes (KU-0063794 and KU-0068650) demonstrate in vitro and ex vivo anti-keloid scar activity

Farhatullah Syed, Hitesh J. Sanganee, Ashwani Bahl, Ardeshir Bayat

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Mammalian target of rapamycin (mTOR) is essential in controlling several cellular functions. This pathway is dysregulated in keloid disease (KD). KD is a common fibroproliferative dermal lesion with an ill-defined treatment strategy. KD demonstrates excessive matrix deposition, angiogenesis, and inflammatory cell infiltration. In KD, both total and phosphorylated forms of mTOR and p70 S6K (Thr421/Ser424) are upregulated. Therefore, the aim of this study was to investigate adenosine triphosphate-competitive inhibitors of mTOR kinase previously unreported in keloid and their comparative efficacy with Rapamycin. Here, we present two mTOR kinase inhibitors, KU-0063794 and KU-0068650, that target both mTORC1 and mTORC2 signaling. Treatment with either KU-0063794 or KU-0068650 resulted in complete suppression of Akt, mTORC1, and mTORC2, and inhibition of keloid cell spreading, proliferation, migration, and invasive properties at a very low concentration (2.5 μmol l -1). Both KU-0063794 and KU-0068650 significantly (P
    Original languageEnglish
    Pages (from-to)1340-1350
    Number of pages10
    JournalJournal of Investigative Dermatology
    Volume133
    Issue number5
    DOIs
    Publication statusPublished - May 2013

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