title: In vitro studies in a myelogenous leukemia cell line suggest an organized binding of geranylgeranyl diphosphate synthase inhibitors.
abstract: A small set of isoprenoid bisphosphonates ethers has been tested in the K562 chronic myelogenous leukemia cell line to determine their impact on isoprenoid biosynthesis. Five of these compounds inhibit geranylgeranyl diphosphate synthase (GGDPS) with IC50 values below 1 μM in enzyme assays, but in cells their apparent activity is more varied. In particular, the isomeric C-geranyl-O-prenyl and C-prenyl-O-geranyl bisphosphonates are quite different in their activity with the former consistently demonstrating greater impairment of geranylgeranylation in cells but the latter showing greater impact in the enzyme assays with GGDPS. Together, these findings suggest an organized binding of these inhibitors in the two hydrophobic channels of the geranylgeranyl diphosphate synthase enzyme.
authors.affiliation: Department of Pharmacology, University of Iowa, 375 Newton Rd, 5219 MERF, Iowa City, IA 52242, USA. Electronic address: jacqueline-reilly@uiowa.edu.
authors.forename: Jacqueline E
authors.initials: JE
authors.lastname: Reilly
authors.affiliation: Department of Chemistry, E531 Chemistry Building, University of Iowa, Iowa City, IA 52242, USA. Electronic address: xiang-zhou@uiowa.edu.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, University of Iowa, 375 Newton Rd, 5219 MERF, Iowa City, IA 52242, USA. Electronic address: huaxiang-tong@uiowa.edu.
authors.forename: Huaxiang
authors.initials: H
authors.lastname: Tong
authors.affiliation: Department of Internal Medicine, University of Iowa, 375 Newton Rd, 5219 MERF, Iowa City, IA 52242, USA. Electronic address: craig.kuder@gmail.com.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Kuder
authors.affiliation: Department of Chemistry, E531 Chemistry Building, University of Iowa, Iowa City, IA 52242, USA. Electronic address: david-wiemer@uiowa.edu.
authors.forename: David F
authors.initials: DF
authors.lastname: Wiemer
authors.affiliation: Department of Pharmacology, University of Iowa, 375 Newton Rd, 5219 MERF, Iowa City, IA 52242, USA; Department of Internal Medicine, University of Iowa, 375 Newton Rd, 5219 MERF, Iowa City, IA 52242, USA; Department of Medicine, Pennsylvania State University, Penn State Hershey Cancer Institute, 500 University Dr, Hershey, PA 17033-0850, USA; Department of Pharmacology, Pennsylvania State University, Penn State Hershey Cancer Institute, 500 University Dr, Hershey, PA 17033-0850, USA. Electronic address: rhohl@hmc.psu.edu.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Hohl
mesh_terms: D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D004987:Ethers / Q000737:chemistry / Q000494:pharmacology*; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D020014:K562 Cells; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D011485:Protein Binding; D017368:Protein Prenylation; D013329:Structure-Activity Relationship; D013729:Terpenes / Q000737:chemistry / Q000494:pharmacology*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D004987:Ethers; D011106:Polyisoprenyl Phosphates; C094135:Rab6 protein; D013729:Terpenes; D051231:Farnesyltranstransferase; D020691:rab GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D018631:ras Proteins; C002963:geranylgeranyl pyrophosphate
keywords: Bisphosphonate; Chronic myelogenous leukemia (CML); Geranylgeranyl diphosphate synthase; Isoprenoid; Protein isoprenylation; Statin