The structures of PIM1 and now PIM2 bound to 1 show a remarkable fit between the inhibitor and the ATP pocket that explains the inhibitor’s potency. Our SAR analysis highlights the promise for further scaffold optimization with both kinases having particular preference for a hydroxyl substituent at the R1 position. The structure of PIM1 in complex with compound 2 showed similar positions for the maleimide group,Niltubacin the cyclopentadienyl ring and the CO ligand, but a 180u flip in the pyridocarbazole moiety that enables two water-mediated hydro-gen bonds to form through the R1 hydroxyl with Glu89. This flexibility indicates further opportunity for inhibitor derivatisation and indeed PIM2 was inhibited most strongly by compound 12 containing an additional carboxyl group at the R2 position. Interestingly, the inhibitor LY3319531 also bound PIM1 in two conformations and the imperfect fit may partially explain its ineffectiveness against PIM2. The primary LY3319531 conformation makes close contact with PIM1 Val126 and the subtle change to Ala122 in PIM2 may be sufficient to destabilize this binding mode. The PIM kinases contain a two-residue insertion in the hinge preceding this position and the smaller PIM2 side chain may allow greater exploitation of this available space. Mouse knockouts lacking all three PIM genes remain viable and fertile but show reduced body size with no hematopoietic response to growth factors. The PIM2 structure and inhibitor data presented here provide further direction to develop well-tolerated drug molecules that stop growth factor independence,VE-821 limit drug resistance and induce tumour apoptosis. Aggregation of hyper-phosphorylated protein tau into filaments and eventually neurofibrillary tangles is characteristic for tauopa-thies, a large and diverse group of neurodegenerative disorders, including Alzheimer’s disease. Primary tauopathies present as clinically variable entities, e.g. Pick’s disease, progressive supranuclear palsy, corticobasal degeneration and frontotemporal dementia, among others. Tauopathy is defined by fibrillar and tangled aggregates of phosphorylated protein tau, which is normally a very soluble protein that binds to microtubules to secure their assembly, stability and spacing.