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Development of selective inhibitors of the isoprenoid biosynthetic pathway and their effects on human‐derived chronic myelogenous leukemia cells
Author(s) -
Reilly Jacqueline E,
Zhou Xiang,
Tong Huaxiang,
Wiemer David,
Hohl Raymond J
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1105.22
Subject(s) - k562 cells , chronic myelogenous leukemia , geranylgeranylation , prenylation , in silico , chemistry , cell culture , biochemistry , leukemia , cell growth , cell , biology , enzyme , immunology , genetics , gene
Proteins dependent on post‐translational geranylgeranylation by the isoprenoid biosynthetic pathway (IBP) are key regulators of malignant cell properties, such as migration, invasion, and proliferation. Nonspecific IBP inhibitors, including statins, have beneficial effects on these malignant cell properties. However, they broadly deplete all mevalonate derivatives and thus affect farnesylated proteins and cholesterol. We have developed two isoprenoid bisphosphonates, XZ‐1–269 and XZ‐1–277, to selectively inhibit geranylgeranyl diphosphate synthase (GGDPS) and diminish only geranylgeranylated proteins. In K562 human‐derived chronic myelogenous leukemia cells XZ‐1–269 impairs geranylgeranylated proteins at 2.5μM as compared to 10μM for digeranyl bisphosphonate (DGBP), and reduces cell viability below 80% at 0.1μM as compared to 10μM for DGBP at 72hrs. Comparatively XZ‐1–277 is inactive, explained by the examination of the crystalline structure of GGDPS. Our findings present a novel, potent compound for selectively reducing geranylgeranylated proteins. Expansion of this family with in silico and experimental structure‐activity relationships will allow for development of even more potent IBP inhibitors. NIH Pharmacological Sciences Training Grant T32 GM067795.