Tricyclic farnesyl protein transferase inhibitors: Crystallographic and calorimetric studies of structure-activity relationships

Crystallographic and thermodynamic studies of farnesyl protein transferase (FPT) complexed with novel tricyclic inhibitors provide insights into the o bserved SAR for this unique class of nonpeptidic FPT inhibitors. The crysta llographic structures reveal a binding pattern conserved across the mono-, di-, and trihalogen series. In the complexes, the tricycle spans the FPT ac tive site cavity and interacts with both protein atoms and the isoprenoid p ortion of bound farnesyl diphosphate. An amide carbonyl, common to the tric yclic compounds described here, participates in a water-mediated hydrogen b ond to the protein backbone. Ten high-resolution crystal structures of inhi bitors 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-o xoethyl]-1-piperidinecarboxamide). Thermodynamic binding parameters show fa vorable enthalpies of complex formation and small net entropic contribution s as observed for 4-[2-[4-(3,10-dibromo-8-chloro-6, 11-dihydro-5H-benzo[5,6 ]-cycloheptal[1,2-b]pyridin-11-ylidene)-1-piperidinyl] -2-oxoethyl]pyridine N-oxide where Delta H-bind(o) = -12.5 kcal/mol and T Delta S-bind(o) = -1. 5 kcal/mol.