The Insulin Receptor (IR) and Type 1 Insulin-Like
Growth Factor Receptor (IGF-1R) are homodimeric α2β2 receptor tyrosine kinases
capable of hybrid heterodimerisation. While both IR and
IGF-1R possess high affinities for their cognate ligands (insulin, and IGF-I and IGF-II, respectively), they may also bind and be activated by reciprocal
ligands. Activation of both homodimeric and hybrid receptors effects the downstream
PI3K-AKT and RAS-RAF-MAPK signaling pathways, having varying effects on
cellular glucose metabolism, differentiation and proliferation. Aberrant signalling
leads to clinical manifestations including diabetes (in the case of IR) and cancer
(in the case of IGF-1R and possibly IR), making these receptors attractive pharmaceutical
targets.
Recent failures of novel therapeutics targeting of IR/IGF-1R highlight the need for highly specific receptor targeting.
Such an approach has been
hampered by an inadequate understanding of the way that each target engages its
respective ligand. Recently it was shown that the primary insulin
binding site is assembled as a tandem element comprising the first leucine-rich
repeat domain (L1) of one receptor monomer in association with the C-terminal
region (αCT)
of the opposite receptor α-chain. Dissociation of the L1 and αCT components will thus specifically abrogate ligand binding.
To further the above idea, a number small molecules were screened for their ability to perturb the interaction between a high-affinity αCT mimetic and the L1 domain within
a truncated IGF-1R system. Identified hits were subsequently
confirmed in a surface plasmon resonance assay targeting the same interaction.
The agonistic or antagonistic potential
of identified compounds as well as their defined binding kinetics
remain to be determined. Further pharmacological refinement of lead compounds
will require accurate pharmacophore generation through x-ray crystallography; of which some progress has been made.