Deltarasin

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

Signaling Pathways >> Metabolic Enzyme/Protease >> Phosphodiesterase (PDE)

Research Areas >> Cancer

Kd: 38 nM (PDEδ)

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 tumour cell xenografts[1].

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.

[1]. Zimmermann G, et al. Small molecule inhibition of the KRAS-PDEδ interaction impairs oncogenic KRAS signalling. Nature. 2013 May 30;497(7451):638-42.

[2]. Agalioti T, et al. Mutant KRAS promotes malignant pleural effusion formation. Nat Commun. 2017 May 16;8:15205. doi: 10.1038/ncomms15205.

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