Rab Geranylgeranylation: a Novel Therapeutic Target in Multiple Myeloma

Rab 香叶基香叶基化：多发性骨髓瘤的新治疗靶点

• 批准号: 8988538
• 负责人: Sarah A Holstein
• 金额: $ 21.66万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2016-08-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8988538
• 关键词: Address; Apoptosis; Apoptotic; Binding; Biological; Biological Assay; Biological Models; Bone Marrow; Cell Death; Cell Survival; Cell physiology; Cells; Cellular Assay; Chemistry; Computer Assisted; Data; Development; Diphosphates; Disease; Drug Combinations; Drug Design; Enzyme Inhibition; Enzymes; Family; Fluorescence; Generations; Goals; Head; Health; Hematologic Neoplasms; Impairment; In Vitro; Individual; Isoprene; Knowledge; Lead; Life; Malignant - descriptor; Malignant Neoplasms; Mediating; Medical; Modeling; Molecular Profiling; Monoclonal Antibodies; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Multiple Myeloma; Pathway interactions; Patients; Plasma Cells; Play; Process; Protein Isoforms; Protein Isoprenylation; Protein Secretion; Proteins; Resolution; Role; Site; Small Interfering RNA; Specificity; Tail; Therapeutic; Therapeutic Agents; Vesicle; Work; Zinc; base; chemical synthesis; combinatorial; cytotoxic; cytotoxicity; design; enzyme pathway; geranylgeranyl pyrophosphate; geranylgeranylation; inhibitor/antagonist; isoprenoid; new therapeutic target; novel; novel therapeutic intervention; novel therapeutics; protein transport; response; therapy development; trafficking

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：多发性骨髓瘤（MM）的特点是恶性浆细胞增殖，分泌大量单克隆蛋白（MP）。到目前为止，还没有针对MP分泌的治疗策略。Rab家族的小gtpase在细胞内囊泡运输中起关键作用。破坏Rab蛋白香叶酰化的药物通过破坏MP分泌诱导MM细胞凋亡，导致MP在细胞内积累并激活未折叠蛋白反应途径（UPR）。香叶基香叶基转移酶II （GGTase II）的有效抑制剂尚未开发，该酶负责翻译后修饰Rab蛋白。此外，关于个体Rabs在调节MP贩运和贩运中的作用知之甚少