Although fragments tend to bind in a highly ligand-efficient manner, their binding is often weak and fragment screening usually relies on sensitive biophysical technologies such as nuclear magnetic resonance, X-ray crystallography, surface plasmon resonance or differential scanning fluorimetry /thermal shift assays. However, fragment screening using high-concentration biochemical assays is increasingly being employed. In this article, we describe the screening of our fragment library against CHK2 using a combination of a high-concentration Amplified Luminescent Proximity Homogeneous Assay Screen kinase assay and a thermal shift assay. A MLN4924 detailed comparison of the AlphaScreenTM and thermal shift screening data revealed that this combination of technologies can help prioritise the most promising fragments by the efficient identification of false positives from each individual screen. In addition, we present the protein-ligand crystal structures of nine fragment hits, all of which bind to the hinge in the CHK2 ATP-binding site. We show that with a focussed similarity search against a moderately sized library of 71,000 lead-like compounds, we were able to identify inhibitors with improved potency with respect to their different parent fragment hits, whilst maintaining ligand efficiency. The crystal LEE011 structure of a quinoxaline-based follow-up compound shows it extending deeply into a previously unexplored hydrophobic pocket above the hinge region, an area that is inaccessible in CHK1 due to its larger gatekeeper +2 residue and therefore could offer a way to enhance CHK2/CHK1 selectivity in future CHK2 inhibitors. Similar to compound 11, compound 14 also interacts with Thr367 via a mediating water molecule, which is not present in the compound 13-bound structure. The electron density of compound 14 indicates that the oxygen atom of its urea moiety points towards the carbonyl group of Met304. This is surprising, as it seems an unfavorable interaction; however, it may account for the slight difference in potency between the two quinoxaline fragments. The amino-quinazoline compound 15 also interacts via one of its ring nitrogen atoms with the amide group of Met304, but in addition its amino-group forms an interaction with Glu308 via a mediating water molecule. The identification of the three pyrazole fragments was reassuring, because the pyrazole moiety is well precedented as a hinge-binding motif in kinase inhibitors. Interestingly, although the pyrazole group in all three hits is the hinge-binding motif and occupies the same space, the three fragments bind in a different manner due to the substitution pattern of each compound.