Identification of CM223 as a new ligand of farnesyl pyrophosphate synthase with improved antiglioma action

Farnesyl Pirophosphate Synthase (FPPS) is a key enzyme in the mevalonate, isoprenoid biosynthesis pathway. FPPS is nowadays the target of bisphosphonates drugs used in osteoporosis disease, nevertheless it is studied as target for anti-cancer therapeutics. N6-Isopentenyladenosine (i6A) is a modified nucleoside exhibiting anti-tumor effects on human and murine cells. Growing biochemical evidence demonstrate the involvement of FPPS protein in i6A anti-tumor action. We previously demonstrated that i6A interacts with FPPS binding site with K D of ~1mM. This interaction corresponded to a modest inhibition of FPPS enzymatic activity. By STD NMR approaches, here we screened newly synthesized analogs of i6A, designed on the basis of i6A-FPPS interaction data. i6A analogues interact with FPPS exhibiting binding mode very similar to i6A. The binding of i6A analogues highlighted the importance of N6-adenosine substituent in the interaction with FPPS binding site. Ideed, introduction on adenosine scaffold of a benzyl moiety induces a significant improvement of interaction with FPPS target. The altered expression of isoprenoid pathway and in particular of FPPS we found in glioma cells and tissue, allowed them to be targeted by the isoprenoid derivatives. As expected CM223 is more effective than i6A in selectively targeting U87 glioma cells but not normal human astrocytes (NHA). This is achieved by the introduction of intrinisc pathway of apoptosis adn inhibition of proliferation along a portein prenylation blockung ad shown by the increase levels of unprenylated Ras and Rap1A. These open the perspective that a modification of the newly introduced benzyl portion of the i6A molecule, may lead to more active molecules in glioma pharmacological research.