DORAMAPIMOD

According to the literature the compound is very unselective. see: Fabian et al.: DOI: 10.1038/nbt1068; Karaman et al.: DOI 10.1038/nbt1358 With PH 797804, VX702, VX745 there are by far more selective compounds available which where in phase II clinical studies as well. For both in vitro (cells) and in vivo (mice) studies with Skepinone-L, a more selective probe is available.

Cell-based modulation of THF-a by BIRB796 in THP1 cells has been demonstrated with an EC50 of 0,01 to 0.065 uM and in human whole blood with an EC50 of 0.78uM( https://pubs.acs.org/doi/10.1021/jm030121k). However, selectivity data presented by Zarrinkar et al (https://www.nature.com/articles/nbt1358) and Fabian et al (https://www.nature.com/articles/nbt1068) show that BIRB796 potently binds 5 kinase targets (DDR1, STK10, JNK2, TIE1 and TNIK) within 30-fold of the affinity of BIRB796 for p38-alpha (0.24nM), and that BIRB796 binds to other kinase targets at concentrations less than 100-fold greater than the affinity for p38-alpha. Until a whole cell chemo-proteomics (or similar) experiment is published to demonstrate cellular target engagement with p38-a and potential off-target kinases, it is this reviewers opinion that cellular pharmacology achieved with BIRB796 cannot be confidently ascribed solely to p38-a binding. Similarly, more data is required to recommend a model organism and dose. For example, demonstration of the extent of on- and off-target engagement in cells and prediction of the extent and duration of on- and off-target inhibition at exposures achieved at the recommended doses in the cited pharmacokinetic studies .