While sequence comparison -and thus, evolutionary similarity -can explain many observations from kinase profiling experiments, other more distantly related off-targets remain undetected. For example, profiling Erlotinib against 48 kinases revealed high affinity against the on-target EGFR (TK group) but also the non-TK off-targets SLK, LOK, and GAK; or the chemical probe SGC-STK17B-1 binds both DRAK2 and CaMMK, although they are dissimilar when judged solely by their sequence. Focusing on the kinase pocket instead of the whole sequence already helps: The 50 most similar kinases to EGFR are only TK kinases when ranked by full-length sequence while listing non-TK kinases when considering the pocket sequence only. The KinCore phylogenetic tree produced by a kinome-wide structureguided MSA overall confirms the assignment from Manning et al. but provides higher precision, e.g. regarding previously unassigned kinases. Schmidt et al. have recently investigated the similarities between a panel of nine kinases -EGFR, ErbB2, PIK3CA, KDR, BRAF, CDK2, LCK, MET, and p38a -based on different pocket encodings, including the pocket sequence identity, pocket structure similarity, interaction fingerprint similarity, and ligand promiscuity. Individual kinase relationships differed according to these different perspectives, while some trends could be observed such as the atypical kinase PIK3CA being an outlier amongst the otherwise typical kinases in this panel.