Multiple myeloma (MM) is characterized by the proliferation of malignant plasma cells which secrete large quantities of monoclonal protein (MP). As yet, no therapeutic strategies have been developed which target MP secretion. The Rab family of small GTPases plays key roles in intracellular vesicle trafficking. Agents which impair the geranylgeranylation of Rab proteins induce apoptosis of MM cells by disrupting MP secretion, resulting in accumulation of MP within the cells and activation of the unfolded protein response pathway (UPR). Potent inhibitors of geranylgeranyltransferase II (GGTase II), the enzyme responsible for post-translationally modifying Rab proteins, have yet to be developed. In addition, little is known regarding the role of individual Rabs in regulating MP trafficking and the effects of selectively disrupting Rab function in MM cells. The following aims are therefore proposed: 1) To develop novel inhibitors of GGTase II and 2) To explore the role of Rabs in regulating MP trafficking in MM cells. The development of novel inhibitors of GGTase II will involve computer-assisted drug design, chemical synthesis, and biological characterization. Agents will be designed and synthesized to contain three moieties: a non-hydrolysable polar head group which will interact with the pyrophosphate recognition site, a zinc-binding motif which will interact with the catalytic zinc site, and an isoprenoid or isoprenoid-like chain which will interact with the terminal isoprene site. The use of a click-chemistry approach will allow for the generation of multiple families of novel agents. A fluorescence-based enzyme assay will be used to determine the inhibitory activity of the compounds. Additional studies will involve determining enzyme specificity, assessing the ability to selectively inhibit Rab geranylgeranylation in MM cells, evaluating the cytotoxic effects, and examining the effects on MP trafficking. To explore the role of individual Rabs in MM cells, the effects of siRNA-mediated silencing of selected Rab isoforms on key cellular processes, including MP trafficking, the UPR, and apoptosis, will be determined. This work will lead to a better understanding of the role of Rabs in MM cells and to the development of novel agents with which to treat patients with MM.
Multiple myeloma, a bone marrow cancer characterized by the secretion of substantial quantities of abnormal antibodies (monoclonal protein), is currently considered to be incurable, and there is a critical need for the development of new treatments. The strategy of inducing myeloma cell death by disrupting monoclonal protein secretion via inhibition of the enzyme geranylgeranyltransferase (GGTase) II is novel. The ultimate goal of the studies described herein is the development of GGTase II inhibitors as a treatment option for multiple myeloma so that these patients may live longer and develop fewer complications from their disease.
|Zhou, Xiang; Ferree, Sarah D; Wills, Veronica S et al. (2014) Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase. Bioorg Med Chem 22:2791-8|