Deltarasin is a small molecular inhibitor of KRAS-PDEδ interaction with Kd of 38 nM for binding to purified PDEδ.

PDEδ:38 nM(Kd)

In liver cells, Deltarasin inhibits the interaction of RAS with PDEδ with KD of 41 nM. Inhibition of PDEδ-KRAS interaction by Deltarasin suppresses proliferation of human pancreatic ductal adenocarcinoma cells that are dependent on oncogenic KRAS. [1]

Deltarasin (10 mg/kg i.p.) impairs dose-dependent tumor growth in nude mice bearing subcutaneous human Panc-Tu-I tumor cell xenografts [1]. The finding may inspire novel drug discovery efforts aimed at the development of drugs targeting oncogenic RAS.

Kd?values are measured by fluorescence polarization measurements. For direct titrations, increasing amounts of PDEδ are added to a solution containing 50-100?nM labelled small molecule in 200?μL PBS buffer. For displacement titrations, increasing amounts of the small molecules in DMSO are directly added to fluorescein-labelled atorvastatin (24?nM) and His6-tagged PDEδ (40?nM) in 200?μL PBS-buffer (containing 0.05% CHAPS, 1% DMSO), keeping the concentration of fluorescein-labelled atorvastatin, PDEδ and DMSO constant. For Kd?measurements using isothermal titration calorimetry, PDEδ protein (280?μM) is titrated to small molecule (30?μM) in Tris/HCl buffer (temperature 25°C). In the Tm shift assays, protein melting points are detected by circular dichroism spectroscopy in the presence of small molecules.