Kinase experiment:

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℃). In the Tm shift assays, protein melting points are detected by circular dichroism spectroscopy in the presence of small molecules.

Deltarasin hydrochloride is a selective inhibitor of KRAS-PDEδ interaction with IC50 value of 41±12 nM [1].

KRAS, also known as V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog, is a protein and works as a molecular on/off switch whose mutant is an essential step in the development of many cancers. PDEδ (prenyl binding protein) controls the spatial organization of K-Ras, which enhances Ras diffusion in the cytosol. Inhibition of the Ras-PDEδ interaction by small molecules impairs Ras localization and signaling has becoming a promising strategy to treat cancers in clinic [1, 2].

Deltarasin hydrochloride is a potent KRAS-PDEδ interaction inhibitor. When tested with human pancreatic ductal adenocarcinoma cells Deltarasin hydrochloride showed inhibition on KRAS-PDEδ interaction to inhibit oncogenic RAS signaling and suppressed cell proliferation by binding to PDEδ with Kd value of 41 nM [1].

In nude mice model with Panc-Tu-I xenograft, administration of Deltarasin hydrochloride (10, 15 mg/kg) impaired cells growth and decreased tumor volume after 9 days in a dose-dependent manner [1].

References:
[1].  Zimmermann, G., et al., Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling. Nature, 2013. 497(7451): p. 638-42.
[2].  The KRAS-PDEdelta interaction is a therapeutic target. Cancer Discov, 2013. 3(7): p. Of20.