Is PDGFR an important target for E-3810?

Dear Sir, In the issue Journal of Cellular and Molecular Medicine, Zhou et al. [1] reported the preclinical characterization of AL3810, an orally bioavailable 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 antitumor activity through the inhibition of VEGFR and FGFR tyrosine kinases. 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 PDGFRα and β. As shown in the attached Table ​Table1,1, 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 PDGFRα and β 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 immunosorbent assay-ELISA) and all the tests were performed at fixed ATP concentration (5 μM), 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 phosphorylation 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. Table 1 In vitro drug IC50s on different kinases reported by the two papers A further interesting piece of information provided by Zhou et al. was that the drug reduced the number of perycites, assessed as PDGFRβ positive cells in tumour xenografts. This is in principle certainly correct [3]; however, since no double immunostaining of CD31 and PDGFRβ 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 biochemical data have been presented. Probably, xenograft tumours taken at different time points from the start of the treatment with E-3810 and the double CD31 and PDGFRβ immuno-staining would help to better define if the PDGF-PDGFR pathway can be directly inferred by E-3810. However, as consistently indicated, this new tyrosine kinase inhibitor has a good pharmacological profile and an outstanding antitumor activity in different experimental systems. The ongoing early clinical investigations confirm the good toxicity profile of E-3810 and support the view that the drug acts by inhibiting VEGFR and FGFR inducing a marked antitumor activity in cancer patients with tumour FGFR amplification even if heavily pretreated with standard chemotherapy and anti-angiogenic therapies [4].