Accordingly, IGF-1 shows promise in the treatment of both insulin-dependent (type I) diabetes and non-insulin-dependent (type II) diabetes. However, the exogenous administration of IGF-1 may cause allergic responses, hypoglycemia, and other health problems, just as injections of insulin do.

Set my IGF-1 free! NBI-31772 binds to all six proteins that readily associate with insulin-like growth factor-1, thereby freeing the naturally occurring hormone to counteract symptoms of diabetes.

To avoid such complications, Nicholas Ling and colleagues from Neurocrine Biosciences, Inc. (San Diego, CA) decided to use IGF-1 molecules naturally found in the body. It is known that there is a large pool of endogenous IGFs that could potentially be used to elicit beneficial effects, but much of this hormone is associated with one or more of six high-affinity IGF-binding proteins, which circulate in the bloodstream and interstitial fluids, neutralizing its bioactivity.

Therefore, the researchers came up with the idea of identifying specific ligands that can displace IGF-1 from these proteins by binding directly to them. To find such ligands, high-throughput screening of about 85,000 compounds was performed against the six IGF-binding proteins (J. Biol. Chem. 2001, 276, 32419–32422). This search proved to be successful: A nonpeptide tricyclic ligand called NBI-31772, actually a derivative of one of the library compounds, was found, which displaces IGF-1 from all six binding proteins at low nanomolar concentrations.

Furthermore, an in vitro cell proliferation assay showed that NBI-31772 dose-dependently releases IGF-1 in a bioactive form. Hence, the compound could serve as a promising lead for the design of novel antidiabetic small-molecule drugs. The researchers think that this therapeutic strategy may be preferable to exogenous administration of insulin or IGF-1, because a “ceiling effect” is reached when all endogenous IGFs are released from the circulating IGF-binding proteins.