Structure-based identification of novel geranylgeranyl diphosphate synthase inhibitors for multiple myeloma treatment

Multiple myeloma (MM) is a devastating hematological malignancy resulting from the uncontrolled clonal expansion of antibody-producing plasma cells. Due to the high burden on the cellular proteogenesis machinery, even slight disturbances to the protein synthesis and degradation balance result in the induction of apoptosis in MM cells. The high level of secreted protein synthesis renders Rab proteins, membrane-delimited small GTPases involved in cellular protein trafficking, viable targets for MM treatment. Importantly, geranylgeranyl diphosphate synthase (GGPPS) produces the post-translational modification moiety required for Rab proteins' membrane association and function. Previously we determined the high-resolution crystal structure of the tri-partite complex between GGPPS, the bisphosphonate drug ibandronate, and magnesium ions. This structure revealed the molecular determinants underlying the complex formation and inhibitory mechanism. However, the potential use of bisphosphonates for GGPPS inhibition in MM treatment is hampered by its limited distribution to bone tissue. Here, to identify novel GGPPS inhibitors as possible MM treatments,we conducted in silico docking of ~2.2 million drug-like molecules to the GGPPS active site. In parallel, we screened 22,000 compounds using an in-house developed fluorescence-based high-throughput screening (HTS) campaign. These screens resulted in the identification of drug-like compounds sharing a common sub-structure for downstream hit-to-lead development. Our robust approach, combining structural and functional assays, forms a firm stepping stone towards the rational structure-based development of novel GGPPS modulators to expand the therapeutic armamentarium offered for MM patients.