Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein.

Stapled-peptides have emerged as an exciting class of molecules which can modulate protein-protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions. This recognition element is a major molecular determinant underlying the improved binding kinetics of these peptides with eIF4E. The interactions were further exploited by designing features in the peptides to attenuate disorder and increase helicity which collectively resulted in the generation of a distinct class of hydrocarbon stapled-peptides targeting eIF4E. This study details new insights into the molecular basis of stapled-peptide: eIF4E interactions and their exploitation to enhance promising lead molecules for the development of stapled-peptide compounds for oncology.

IRC-083927 is a new tubulin binder that inhibits growth of human tumor cells resistant to standard tubulin-binding agents.

Tubulin is a validated target for antitumor drugs. However, the effectiveness of these microtubule-interacting agents is limited by the fact that they are substrates for drug efflux pumps (P-glycoprotein) and/or by the acquisition of point mutations in tubulin residues important for drug-tubulin binding. To bypass these resistance systems, we have identified and characterized a novel synthetic imidazole derivative IRC-083927, which inhibits the tubulin polymerization by a binding to the colchicine site. IRC-083927 inhibits in vitro cell growth of human cancer cell lines in the low nanomolar range. More interesting, it remains highly active against cell lines resistant to microtubule-interacting agents (taxanes, Vinca alkaloids, or epothilones). Such resistances are due to the presence of efflux pumps (NCI-H69/LX4 resistant to navelbine and paclitaxel) and/or the presence of mutations on beta-tubulin and on alpha-tubulin and beta-tubulin (A549.EpoB40/A549.EpoB480 resistant to epothilone B or paclitaxel). IRC-083927 displayed cell cycle arrest in G(2)-M phase in tumor cells, including in the drug-resistant cells. In addition, IRC-083927 inhibited endothelial cell proliferation in vitro and vessel formation in the low nanomolar range supporting an antiangiogenic behavior. Finally, chronic oral treatment with IRC-083927 (5 mg/kg) inhibits the growth of two human tumor xenografts in nude mice (C33-A, human cervical cancer and MDA-MB-231, human hormone-independent breast cancer). Together, the antitumor effects induced by IRC-083927 on tumor models resistant to tubulin agents support further investigations to fully evaluate its potential for the treatment of advanced cancers, particularly those resistant to current clinically available drugs.

Butyl 2-(4-[1.1'-biphenyl]-4-yl-1H-imidazol-2-yl)ethylcarbamate, a potent sodium channel blocker for the treatment of neuropathic pain.

A series of 4-arylimidazole carbamates was synthesized and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to the identification of compound 10, a potent Na+ channel blocker which was efficacious in pain models in vivo.

2-Alkyl-4-arylimidazoles: structurally novel sodium channel modulators.

A series of 2-alkyl-4-arylimidazoles were prepared and their binding affinities to the site-2 sodium (Na+) channel were determined. SAR studies led to highly potent Na+ channel blockers.