The project that we propose focuses on the development of small molecules that stabilize FGE-structure and act as pharmacological agents for therapeutic intervention of MSD. Recent key results published by us and others, have unambiguously shown that most of the MSD cases are caused by SUMF1 missense mutations which result in unstable FGE protein with low catalytic functionality. Our therapeutic strategy is based on the rationale that small molecules strongly binding at the surface of FGE mutants will act as a “pharmacological chaperone” thereby stabilizing the protein and rescuing its catalytic activity towards sulfatase substrates. In the proposed project, we have put forward a rationally designed approach for identification, development and evaluation of FGE-targeting drug-like molecules. At the core of the project are fragment screening technologies to identify small molecules that could be developed into sought drugs. This will involve 1) performing screens to identify molecular entities binding at the FGE surface and characterizing their potency and mode of action using biophysical and structural techniques, 2) their synthetic optimization into chemical probes/drugs binding and stabilizing FGE, and 3) the evaluation of their therapeutic effect in MSD-derived cell lines and MSD animal models. In a pilot study, we have already established and performed a fragment screen with recombinant FGE and identified small molecule entities that bind to FGE, which will be subjected to iterative characterization and optimization as detailed above. Further supporting our rationale, the applicants recently applied this small molecule stabilization strategy to successfully rescue the activity of an unstable p53 mutant in cancer. The past successes and lessons learnt from the p53 project will be valuable to develop the sought FGE rescue drugs. This project brings together the synergistic expertise of the applicants spanning across complementary disciplines, including synthetic chemistry, biophysics, biochemistry, computational studies, molecular/structural/cell biology and clinical sciences.
