Here we report a fragment screening platform, PhABits, where a library of photoreactive fragments are screened in the presence of purified protein. Hits can be detected by intact protein LC-MS enabling identification of known and new chemotypes. Follow-up studies allow determination of binding affinities and the sites of crosslinking. In order to develop fragments into more potent binders, hit PhABits can subsequently be employed as reporter ligands in a MS-based displacement assay. The PhABit platform enables efficient identification of fragment-protein interactions for binding sites that do not contain cysteine residues. Moreover, the approach enabled rapid detection of fragment hits for KRas4B G12D , which is widely considered to be a poorly tractable target.