Study of the Selectivity of Insulin-Like Growth Factor-1 Receptor (IGF1R) Inhibitors

Abstract

Abstract:The insulin-like growth factor-1 receptor (IGF1R) is a drug target for oncology, and many studies are ongoing to identify compounds that inhibit its tyrosine kinase activity. IGF1R is highly homologous to the insulin receptor (IR) and IGF1R inhibition might be beneficial for patients, while IR inhibition may lead to limiting toxicity. Therefore selectivity for IGF1R over IR is the aim for drug design in this context. A few compounds that selectively inhibit IGF1R over IR in cells have been identified, but none of them show the same levels of selectivity in enzymatic assays. To determine whether this discrepancy is linked to the conditions used in the enzymatic assays, we have studied the interaction between known IGF1R inhibitors (NVP-AEW541, OSI906, AG538, NVP-TAE226) and phosphorylated/unphosphorylated IGF1R/IR proteins with both biophysical (isothermal calorimetry and surface plasmon resonance) and enzymatic methods. In this report, we describe the results of this study and comment on the different degrees of selectivity IGF1R versus IR measured in biochemical and cellular assays. Finally, our study provides new information on the biochemical and mechanism of action of these small molecular weight IGF1R inhibitors.

Identification of Novel IGF1R Kinase Inhibitors by Molecular Modeling and High-Throughput Screening

“…Interestingly, compounds T1 and T3 exhibited a substantially stronger (5-10-fold) inhibition of InsR versus IGF1R in our experiments. This selectivity was similar or higher than that of almost all the known small molecule inhibitors of IGF1R demonstrated in a valid biochemical assay [ 23 ], apparently reflecting a very high degree of similarity between the receptors at their catalytic sites and in their close vicinity. The single concentration data on the inhibition of the more distantly related tyrosine kinases Met, BTK, and Syk ( Table 2 ) suggests no inhibition (compounds L1, T3) or weak inhibition for some of these kinases, with estimated IC 50 values in excess of 50 μM.…”