Is PDGFR an important target for E-3810?

In the issue Journal of Cellular and Molecular Medicine, Zhou et al. [1] reported the preclinical characterization of AL3810, an orally bio-available small molecule inhibitor of tyrosine kinases involved in angiogenesis. The paper confirms most of the data that we have recently reported on the same compound [2] – that we named E-3810 – as correctly quoted by the authors. We were pleased to see that, in spite of the different experimental models used and of the different methodologies applied, Zhou et al. reported a consistent set of data confirming that E-3810 has a potent anti-angiogenic and antitu-mor activity through the inhibition of VEGFR and FGFR tyrosine kinas-es. However, in contrast to what observed and reported by us, we noticed that Zhou et al. observed that the drug is also an inhibitor of PDGFRa and b. As shown in the attached Table 1, the drug concentrations that inhibited the kinase activity reported by Zhou et al. [1] and by us [2] were in the same nM range for VEGFR and FGFR kinases; on the contrary for the PDGFRa and b kinases these concentrations were much lower in Zhou et al. paper than in our report. The discrepancy could be related to the different biochemical assays used in the two studies; in fact, Zhou et al. used a colorimetric assay (enzyme-linked immuno-sorbent assay-ELISA) and all the tests were performed at fixed ATP concentration (5 lM), whereas we used more sensitive radiometric assays, with ATP concentrations always very close to single kinases Km. On the other hand, it should be noted that when the inhibition of the kinase activity was assessed in cells, the data obtained in the two studies were quite similar for the VEGF-dependent VEGFR phosphory-lation and also for PDGFR phosphorylation: Zhou et al. found the latter inhibited at concentrations one log higher (i.e. 100 nM), i.e., very close to those found by us in both in in vitro biochemical and cellular assays. A further interesting piece of information provided by Zhou et al. was that the drug reduced the number of perycites, assessed as PDGFRb positive cells in tumour xenografts. This is in principle certainly correct [3]; however, since no double immunostaining of CD31 and PDGFRb positivity were presented, it may be argued that the reduction in perycites is an indirect effect related to the endothelial cell loss induced by the inhibition of the VEGF-VEGFR pathway, for which clear …