Target engagement is a fundamental paradigm in drug discovery. A significant portion of projects fail to reach the clinic due to lack of efficacy or failure to show the lead candidate is interacting with the intended target in a more complex environment. Using the proven CEllular Thermal Shift Assay (CETSA) technology to measure target engagement in various matrixes, such as tissues, intact cells or lysates is increasingly common for SAR studies and lead optimisation. It is also possible to inform early stage programs with CETSA technologies and investigate in-situ ligandability. This study looks to investigate a well-established oncology target using CETSA high throughput platform (HT). CETSA HT measures direct target engagement through interaction of the protein and molecule after a heat challenge, with versatile readouts applicable to HTS and miniaturisation for robotic platforms. Assay development for CETSA HT includes development of HTS off-the-shelf kit formats and in this project, investigations into target engagement of fragments within a cellular environment. These target engagement studies are not reliant on in-vitro and often abstract functional screens or methods, often limiting to certain protein classes.