Axxam and Polyphor initiated a joint three-year research program focused on the discovery and development of GLP-1 receptor modulators for treating type 2 diabetes. The InsuSecret project will be funded to the tune of about €3.1 million (nearly $4.5 million) by the Eurostars program, a joint initiative between EUREKA and the EU’s Seven Framework Program (FP7). The diabetes program follows on from the firms’ existing, multiple-disease ion-channel drug discovery alliance, which was signed back in April 2010.
The diabetes program will investigate different potential mechanisms of action on the GLP-1 receptor, including allosteric modulators, or inhibitors for receptor desensitization. “If this research program yields promising GLP-1R modulators, Axxam and Polyphor will aim to establish a research alliance with a pharma partner for further development and commercialization,” notes Daniel Obrecht, Ph.D., Polyphor co-founder and CSO.
Italy-based Axxam is leveraging a suite of discovery platforms to identify drugs in fields including pain, metabolic disorders, and autoimmune diseases. Its technologies are also offered through services for assay development, high-throughput screening, compound profiling, and hit-to-lead development. The firm claims to have in place a number of technologies particularly suited to GPCR research, including its calcium ion-activated photoprotein Photina® platform, for measuring GPCR activation, and the universal reporter cell line chAMPion, which couples the photoprotein technology with the sensitivity of cyclic nucleotide-gated channels for measuring cAMP levels. Photina also forms the basis of Axxam’s PhotoStem mouse embryonic stem cell line, and PhotoTopo® transgenic mouse model.
Within the last two months Axxam has separately received drug discovery funding from both the Alzheimer’s Drug Discovery Foundation and FastForward, a U.S.-based nonprofit organization established by the National Multiple Sclerosis Society and Merck Serono. The grants will support programs targeting the axonal sodium-calcium exchanger NCX1 for MS therapy, and the brain inflammatory target P2X7 for the potential treatment of Alzheimer disease and other neurodegenerative disorders.
Swiss firm Polyphor is exploiting its PEMfinder® and MacroFinder® libraries of macrocyclic molecules and associated platforms to develop an in-house and partnered pipeline of compounds for applications in fields ranging from hematopoietic stem cell transplant to cancer, tissue repair, inflammation, COPD, and bacterial infections.
While both platforms are designed to modulate complex protein-protein interaction (PPI) targets, PEMfinder addresses mainly extracellular large surface PPI targets, whereas MacroFinder molecules are designed to penetrate into the cells to hit intracellular PPIs and with the potential for oral delivery, Polyphor claims. PEM (protein epitope mimetics) compounds are fully synthetic cyclic peptide-like molecules that mimic the beta-hairpin and alpha-helix structural motifs involved in PPIs. The PEMfinder library comprises over 15,000 PEMS, which the firm says are particularly suited for discovery projects against GPCRs with large ligand-binding sites, ion channels, and other targets involving PPIs.
MacroFinder molecules are fully synthetic compounds comprising a number of subunits that can be assembled in a modular fashion, and which display functional groups. The compound library comprises molecules of variable ring size with a molecular weight of 400–800 Daltons, and semi-rigid backbone conformations induced by built-in structural constraints. Polyphor claims the nature of the molecules allows a high degree of conformational fine tuning through variation of ring size and stereochemistry of modular building blocks.
The firm’s lead clinical-stage candidate is a CXCR4 antagonist (POL6326), which is in Phase II trials in patients undergoing hematopoietic stem cell transplantation, and is also being evaluated in preclinical in vivo studies for indications including cancer, tissue repair, inflammation, and drug-eluting stents. Polyphor’s lead antibiotic candidate, POL7080, is in Phase I studies for the treatment of Pseudomonas infections. A protease inhibitor POL6014 is in preclinical development.