The identification of small molecule inhibitors for the novel cancer target UROS

Elevated heme metabolism has been implicated in tumour development and progression, therefore proteins in the heme synthesis pathway are potential targets for cancer therapy. Uroporphyrinogen III synthase (UROS), the third enzyme in the pathway, is of particular interest as it is often found to be over-expressed in different cancer types, and expression levels correlate with a lower survival rate. Inhibiting UROS expression could therefore lead to better survival rates in cancer patients, providing a precision medicine. Conservation, topology and probe interaction energy modelling of UROS in partnership with molecular dynamic simulations determined the conformational changes of UROS, in response to ligand binding, and together with in silico docking of the natural ligand and product of UROS (Hydroxymethylbilane and Uroporphyrinogen III, respectively) confirmed the suggestion that the binding pocket exists between two lobes. Molecular dynamic simulations determined the conformational changes of UROS, in response to ligand binding, and together with in silico docking of the natural ligand and product of UROS (Hydroxymethylbilane and Uroporphyrinogen III, respectively) confirmed the predicted binding site. Ligands from the FDA database were docked in silico and several potential hits were identified. Importantly, thermal shift assays demonstrated that these molecules bind to UROS and have the potential to be competitive inhibitors and therefore reduce the level of heme produced. Further studies on the efficiency of the hits, as inhibitors of heme synthesis, are needed and hit to lead optimisation should follow.