title: Adenosine-derived inhibitors of 78 kDa glucose regulated protein (Grp78) ATPase: insights into isoform selectivity.
abstract: 78 kDa glucose-regulated protein (Grp78) is a heat shock protein (HSP) involved in protein folding that plays a role in cancer cell proliferation. Binding of adenosine-derived inhibitors to Grp78 was characterized by surface plasmon resonance and isothermal titration calorimetry. The most potent compounds were 13 (VER-155008) with K(D) = 80 nM and 14 with K(D) = 60 nM. X-ray crystal structures of Grp78 bound to ATP, ADPnP, and adenosine derivative 10 revealed differences in the binding site between Grp78 and homologous proteins.
authors.affiliation: Vernalis (R&D) Ltd., Granta Park, Great Abington, Cambridge, CB21 6GB, UK. a.macias@vernalis.com
authors.forename: Alba T
authors.initials: AT
authors.lastname: Macias
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Williamson
authors.forename: Nicola
authors.initials: N
authors.lastname: Allen
authors.forename: Jenifer
authors.initials: J
authors.lastname: Borgognoni
authors.forename: Alexandra
authors.initials: A
authors.lastname: Clay
authors.forename: Zoe
authors.initials: Z
authors.lastname: Daniels
authors.forename: Pawel
authors.initials: P
authors.lastname: Dokurno
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Drysdale
authors.forename: Geraint L
authors.initials: GL
authors.lastname: Francis
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Graham
authors.forename: Rob
authors.initials: R
authors.lastname: Howes
authors.forename: Natalia
authors.initials: N
authors.lastname: Matassova
authors.forename: James B
authors.initials: JB
authors.lastname: Murray
authors.forename: Rachel
authors.initials: R
authors.lastname: Parsons
authors.forename: Terry
authors.initials: T
authors.lastname: Shaw
authors.forename: Allan E
authors.initials: AE
authors.lastname: Surgenor
authors.forename: Lindsey
authors.initials: L
authors.lastname: Terry
authors.forename: Yikang
authors.initials: Y
authors.lastname: Wang
authors.forename: Mike
authors.initials: M
authors.lastname: Wood
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Massey
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D000255:Adenosine Triphosphate / Q000737:chemistry; D000266:Adenylyl Imidodiphosphate / Q000737:chemistry; D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans / Q000138:chemical synthesis* / Q000737:chemistry; D050883:HSC70 Heat-Shock Proteins / Q000737:chemistry; D018840:HSP70 Heat-Shock Proteins / Q000737:chemistry; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000737:chemistry; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D013816:Thermodynamics
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005663:Furans; D050883:HSC70 Heat-Shock Proteins; D018840:HSP70 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D020033:Protein Isoforms; D011687:Purines; D000266:Adenylyl Imidodiphosphate; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases