The KRAS oncogene product is considered a major target in anticancer drug discovery. Interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes. Deltarasin is an inhibitor of the KRAS-PDEδ interaction to impair oncogenic KRAS signalling.
In vitro: Within a minute, 5 mM of deltarasin completely inhibited PDEδ-KRAS interaction and released the insolubilized mCitrine-RHEB/KRAS6Q to the endomembrane system. This showed that deltarasin interfered with the binding of KRAS to PDEδ in cells and thereby inhibited its solubilization [1].
In vivo: A clear dose-dependent reduction in Panc-Tu-I tumour growth rate could be observed in deltarasin treated mice with respect to the vehicle-injected controls, where the growth of tumours in mice that were treated with 10mg kg/1 BID deltarasin was almost completely blocked [1].
Clinical trial: No clinical data are available.
Reference:
[1] Zimmermann G, Papke B, Ismail S, Vartak N, Chandra A, Hoffmann M, Hahn SA, Triola G, Wittinghofer A, Bastiaens PI, Waldmann H. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature. 2013;497(7451):638-42.