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.

Structures of Cryptococcus neoformans Protein Farnesyltransferase Reveal Strategies for Developing Inhibitors That Target Fungal Pathogens

“…3b and 7) and may accommodate the displaced iso-prenylated product, similar to hFTase. By analogy to similar studies in hFTase (26,49), this groove may play an important role in inhibitor binding in CnFTase. Significant differences between the protein sequences are observed in the peptide binding site and product exit groove.…”

“…Helix 4␣-5␣ Substrate-dependent Conformational ChangeNo ligand-dependent conformational changes have been observed crystallographically in human protein prenyltransferase enzymes (12,23,26,28,36,49,(52)(53)(54). Throughout the reaction cycle and upon binding of inhibitors, these enzymes apparently remain rigid, whereas their substrates exhibit significant rearrangements during chemistry.…”

Cdk inhibitors, roscovitine and olomoucine, synergize with farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of human cancer cell lines

“…FTI binds to protein farnesytransferase (FTase) that catalyzes farnesylation of proteins ending with the C-terminal CAAX motif (C is cysteine, A is aliphatic amino acid and X is the C-terminal amino acid) (Zhang and Casey, 1996). Recently, structures of the co-crystals formed between FTase, CAAX peptide and a tricyclic type FTI have been determined (Strickland et al, 1999). The CAAX ending proteins include Ras-superfamily G-proteins such as Ras and RhoB as well as enzymes such as tyrosine phosphatase and inositol lipid 5-phosphatase (Der et al, 1996;Lebowitz and Prendergast, 1998).…”

Thematic review series: Lipid Posttranslational Modifications. Structural biology of protein farnesyltransferase and geranylgeranyltransferase type I

“…Design efforts from Schering-Plough have resulted in a number of FTase inhibitors, of which a series of tricyclic compounds have been structurally characterized (144). These compounds are composed of three connected rings, with a tail containing two or more rings extending from the central seven carbon ring, representing a series of mono-, di-, and trihalogenated species.…”