SU6656

This is a probe first described in 2000. It is useful only as an historical probe, one that was used in hundreds of papers before it became clear that kinase inhibitors could be quite selective and before the off-targets of this compound were well known (see e.g.doi: 10.1042/BJ20070797, which found many off-targets in a relatively small screen of 70-80 kinases Kinase/IC50(microM)/ATP concentration in the assay Src 0.10 50 Lck 0.15 50 Aurora B 0.019 20 Aurora C 0.017 5 BRSK2 0.10 50 MST2 0.11 50 AMPK 0.11 50)

Whilst SU-6656 has been shown to inhibit four of the nine Src family kinases with an IC50 less than 1 uM and does not inhibit PDGFRβ at 10 uM, it also hits a number of additional kinases such as Abl, Met, and FGFR1 with insufficient selectivity (IC50s within 30-fold of the Src family kinases). Other studies have shown that it inhibits AMPK and Aurora kinases. This level of inhibition for non Src family kinases means that SU-6656 is not selective enough to qualify as a reliable chemical probe in cells or model organisms. The chemical probe eCF506 should be preferred for interrogating Src family kinases at the current time, with a need for Src family kinase inhibitors showing demonstrated selectivity.

SU6656 inhibits kinases of the Src family, with some selectivity over PDGFR. However, SU6656 also inhibits BRSK2 and MST2 with similar potency to its inhibition of Src and Lck. Furthermore, SU6656 inhibits Aurora B/C kinases even more potently than Src and Lck. Other kinases such as CaMKKα, CaMKKβ, CHK2 and SRPK1 are targeted by SU6656 as well (J Biochem 2007; 408: 297-315). Given this lack of selectivity, SU6656 is not suitable for studying Src mediated signalling in cells and data obtained in cells/model organisms with SU6656 must be interpreted with great caution. It is also important to note the direct binding and paradoxical activation of AMPK by SU6656 (Cell Chem Biol 2017, 24: 813-824), which could further confound cellular data obtained with SU6656.