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Potent Dual Inhibitors of TORC1 and TORC2 Complexes (KU-0063794 and KU-0068650) Demonstrate in Vitro and Ex Vivo Anti-Keloid Scar Activity

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, Subir Singh, Ashwani Bahl, Ardeshir Bayat

J Invest Dermatol. 2013 May;133(5):1340-50.

PMID: 23303455

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<0.05) inhibited cell cycle regulation and HIF1-α expression compared with that achieved with Rapamycin alone. In addition, both compounds induced shrinkage and growth arrest in KD, associated with the inhibition of angiogenesis, induction of apoptosis, and reduction in keloid phenotype-associated markers. In contrast, Rapamycin induced minimal antitumor activity. In conclusion, potent dual mTORC1 and mTORC2 inhibitors display therapeutic potential for the treatment of KD.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP938440643-A	KU 0063794		938440-64-3	Price

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