title: Tricyclic farnesyl protein transferase inhibitors: crystallographic and calorimetric studies of structure-activity relationships.
abstract: Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the observed SAR for this unique class of nonpeptidic FPT inhibitors. The crystallographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT active site cavity and interacts with both protein atoms and the isoprenoid portion of bound farnesyl diphosphate. An amide carbonyl, common to the tricyclic compounds described here, participates in a water-mediated hydrogen bond to the protein backbone. Ten high-resolution crystal structures of inhibitors complexed with FPT are reported. Included are crystallographic data for FPT complexed with SCH 66336, a compound currently undergoing clinical trials as an anticancer agent (SCH 66336, 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-yl)-1-piperidinyl]-2-oxoethyl]-1-piperidinecarbo xamide ). Thermodynamic binding parameters show favorable enthalpies of complex formation and small net entropic contributions as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo[5, 6]cyclohepta[1, 2-b]pyridin-11-ylidene)-1-piperidinyl]-2-oxoethyl]pyridine N-oxide where DeltaH degrees bind = -12.5 kcal/mol and TDeltaS degrees bind = -1.5 kcal/mol.
authors.affiliation: Department of Structural Chemistry, Schering-Plough Research Institute, Kenilworth, New Jersey 07033, USA.
authors.forename: C L
authors.initials: CL
authors.lastname: Strickland
authors.forename: P C
authors.initials: PC
authors.lastname: Weber
authors.forename: W T
authors.initials: WT
authors.lastname: Windsor
authors.forename: Z
authors.initials: Z
authors.lastname: Wu
authors.forename: H V
authors.initials: HV
authors.lastname: Le
authors.forename: M M
authors.initials: MM
authors.lastname: Albanese
authors.forename: C S
authors.initials: CS
authors.lastname: Alvarez
authors.forename: D
authors.initials: D
authors.lastname: Cesarz
authors.forename: J
authors.initials: J
authors.lastname: del Rosario
authors.forename: J
authors.initials: J
authors.lastname: Deskus
authors.forename: A K
authors.initials: AK
authors.lastname: Mallams
authors.forename: F G
authors.initials: FG
authors.lastname: Njoroge
authors.forename: J J
authors.initials: JJ
authors.lastname: Piwinski
authors.forename: S
authors.initials: S
authors.lastname: Remiszewski
authors.forename: R R
authors.initials: RR
authors.lastname: Rossman
authors.forename: A G
authors.initials: AG
authors.lastname: Taveras
authors.forename: B
authors.initials: B
authors.lastname: Vibulbhan
authors.forename: R J
authors.initials: RJ
authors.lastname: Doll
authors.forename: V M
authors.initials: VM
authors.lastname: Girijavallabhan
authors.forename: A K
authors.initials: AK
authors.lastname: Ganguly
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D018360:Crystallography, X-Ray; D003497:Cyclic N-Oxides / Q000737:chemistry*; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D006860:Hydrogen Bonding; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry*; D017368:Protein Prenylation; D011725:Pyridines / Q000737:chemistry*; D013816:Thermodynamics; D003986:Dibenzocycloheptenes
chemical_list: D019883:Alkyl and Aryl Transferases; D000970:Antineoplastic Agents; D003497:Cyclic N-Oxides; D004791:Enzyme Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010880:Piperidines; D011725:Pyridines; C119795:4-(2-(4-(3,10-dibromo-8-chloro-6,11-dihydro-11H-benzo(5,6)cyclohepta(1,2-b)pyridin-11-ylidine)-1-piperidinyl)-2-oxoethyl)pyridine N-oxide; C064911:p21(ras) farnesyl-protein transferase; C115354:lonafarnib; D003986:Dibenzocycloheptenes