A lead molecule in an AstraZeneca preclinical program in development for respiratory disease induced bone marrow (BM) toxicity (reduced hematopoietic cellularity) in a rat investigative toxicology study (iTox). We aimed to understand the mechanism behind BM toxicity and the potential for clinical development of the compound. In vitro secondary pharmacology screening identified cKIT as an off-target. Applying chemoproteomics selectivity profiling on BM and lung tissue (collected in the rat iTox) confirmed dose-dependent inhibition of cKIT in BM and correlation with BM toxicity, and demonstrated that the compound more potently inhibited the primary target in lung vs cKIT in BM. The compound was tested together with Imatinib (a known cKIT inhibitor associated mainly with anaemia in oncology patients) in an in vitro human BM micro-physiological system (MPS) for 28 days. In this system the compound and Imatinib demonstrated concentration and time dependent reduction of hematopoietic progenitors. This experimental data was subsequently fed into a quantitative systems pharmacology model (QST) enabling prediction of the expected clinical exposure leading to a change in patients? hematology over time. The human QST haematopoiesis model, based on BM MPS data and correlation to Imatinib, predicted low/no risk of anaemia or neutropenia at the estimated human therapeutic dose, while a 3x increase of this dose could be associated with mild anaemia. In conclusion, identifying cKIT as an off-target, combining the PK/PD understanding of rat iTOX data and the MPS-based mathematical modelling of clinical haematotoxicity provided confidence to progress the compound into clinical development and informed the Ph1 study design.