Potent, Selective, and Orally Bioavailable Tricyclic Pyridyl Acetamide N -Oxide Inhibitors of Farnesyl Protein Transferase with Enhanced in Vivo Antitumor Activity (original) (raw)
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NMR studies of novel inhibitors bound to farnesyl-protein transferase
Protein Science, 2008
Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cysteine residue located in the carboxyl-terminal tetrapeptide of the Ras oncoprotein. Prenylation of this residue is essential for the membrane association and cell-transforming activities of ras. Inhibitors of FPTase have been demonstrated to inhibit ras-dependent cell transformation and thus represent a potential therapeutic strategy for the treatment of human cancers. The FPTase-bound conformation of a tetrapeptide inhibitor, CVWM, and a novel pseudopeptide inhibitor, L-739,787, have been determined by NMR spectroscopy. Distance constraints were derived from twodimensional transferred nuclear Overhauser effect experiments. Ligand competition experiments identified the NOES that originate from the active-site conformation. Structures were calculated with the combination of distance geometry and restrained energy minimization. Both peptide backbones are shown to adopt nonideal reverseturn conformations most closely approximating a type 111 P-turn. These results provide a basis for understanding the spatial arrangements necessary for inhibitor binding and selectivity and may aid in the design of therapeutic agents.
Journal of Medicinal Chemistry, 1999
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-piperidinecarboxamide). 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 ∆H°b ind ) -12.5 kcal/mol and T∆S°b ind ) -1.5 kcal/mol. . † Abbreviations: farnesyl protein transferase (FPT), farnesyl diphosphate (FPP), concentration of inhibitor to cause 50% inhibition (IC50), structure-activity relationship (SAR), isothermal titration calorimetry (ITC), R-hydroxyfarnesylphosphonic acid (RHFP).
Analysis of two-nucleon transfer reactions in the Ne20+Cd116 system at 306 MeV
Physical Review C
Background: Heavy-ion induced two-nucleon transfer reactions are powerful tools to reveal peculiar aspects of the atomic nucleus, such as pairing correlations, single-particle and collective degrees of freedom, and more. Also, these processes are in competition with the direct meson exchange in the double charge exchange reactions, which have recently attracted great interest due to their possible connection to neutrinoless double-beta decay. In this framework, the exploration of two-nucleon transfer reactions in the 20 Ne + 116 Cd collision at energies above the Coulomb barrier is particularly relevant since the 116 Cd nucleus is a candidate for the double-β decay. Purpose: We want to analyse selected transitions to low-lying 0 + and 2 + states of the residual nuclei in the 116 Cd(20 Ne, 22 Ne) 114 Cd two-neutron pickup and 116 Cd(20 Ne, 18 O) 118 Sn two-proton stripping reactions at 306 MeV incident energy and determine the role of the couplings with inelastic transitions. Methods: We measured the excitation energy spectra and absolute cross sections for the two reactions using the MAGNEX large acceptance magnetic spectrometer to detect the ejectiles. We performed direct coupled reaction channels and sequential distorted wave Born approximation calculations using the double folding São Paulo potential to model the initial and final state interactions. The spectroscopic amplitudes for two-and single-particle transitions were derived by different nuclear structure approaches: microscopic large-scale shell model, interacting boson model-2 and quasiparticle random phase approximation. Results: The calculations are able to reproduce the experimental cross sections for both twoneutron and two-proton transfer reactions provided that the couplings with the inelastic channels are taken into account. A competition between the direct and the sequential process is found in the reaction mechanism. For the two-proton transfer case, the inclusion of the 1g7/2 and 2d5/2 orbitals in the model space is crucial.
Inhibitors of farnesyl:protein transferase—A possible cancer chemotherapeutic
1996
The recent interest in inhibitors of farnesyl:protein transferase (FPTase) has resulted in a better understanding of the enzymology of this protein. Rationally designed inhibitors of prenyl transfer have emerged as potential new drug candidates because of the insight gained over bow a prenyl group is enz3'matically transferred onto a peptide thiol. This paper will explore how advances in our understanding of FPTase mediated catalysis has affected the design of FPTase inhibitors as possible cancer therapeutic agents. Without structural information of the enzyme, substrate analogues comprise the first area of drug design: these include peptidomimetics of the four C-terminal amino acids of rasP21 as well as farnesyl diphosphate analogs. In addition, phosphate anion was found to enhance the inhibitory potency of certain compounds known to be competitive with respect to farnesyl diphosphate and therefore incorporation of the phosphate anion may also provide a basis for improved inhibitor design.
Journal of Medicinal Chemistry, 1997
Scheme 1 a a (a) Bu4NNO3, TFAA; (b) concd HCl, reflux; (c) 4-pyridineacetic acid, DEC, HOBT, NMM; (d) iron fillings, CaCl2.
Journal of Computational Chemistry, 2007
Farnesyltransferase (FTase), an interesting zinc metaloenzyme, has been the subject of great attention in anticancer research over the last decade. However, despite the major accomplishments in the field, some very pungent questions on the farnesylation mechanism still persist. In this study, the authors have analyzed a mechanistic paradox that arises from the existence of several contradicting and inconclusive experimental evidence regarding the existence of direct coordination between the active-site zinc cation and the thioether from the farnesylated peptide product, which include UV-vis spectroscopy data on a Co 2þ -substituted FTase, two X-ray crystallographic structures of the FTase-product complex, and extended X-ray absorption fine structure results. Using high-level theoretical calculations on two models of different sizes, and QM/MM calculations on the full enzyme, the authors have shown that the farnesylated product is Zn coordinated, and that a subsequent step where this Zn bond is broken is coherent with the available kinetic results. Furthermore, an explanation for the contradicting experimental evidence is suggested. q
Journal of Peptide Research, 1999
Conformation of a novel tetrapeptide inhibitor NH2-d-Trp-d-Met-Phe(pCl)-Gla-NH2 bound to farensyl-protein transferase. Abstract: Farnesyl-protein transferase (FPTase) catalyzes the posttranslational farnesylation of the cysteine residue located in the C-terminal tetrapeptide of the Ras oncoprotein. Prenylation of this residue is essential for membrane association and celltransforming activities of ras. Inhibitors of FPTase have been demonstrated to display antitumor activity in both tissue culture and animal models, and thus represent a potential therapeutic strategy for the treatment of human cancers. A synthetic tetrapeptide library, which included an expanded set of 68 L-, Dand noncoded amino acids, has been screened for inhibitors of FPTase activity. The tetrapeptide, NH 2 -D-Trp-D-Met-L-Phe(pCl)-L-Gla-NH 2 was shown to be competitive with the isoprenyl cosubstrate, farnesyl diphosphate (FPP) but not with the peptide substrate, the C-terminal tetrapeptide of the Ras protein. The FPTase-bound conformation of the inhibitor, NH 2 -D-Trp-D-Met-L-Phe(pCl)-L-Gla-NH 2 was determined by NMR spectroscopy. Distance constraints were derived from two-dimensional transferred nuclear Overhauser effect (TRNOE) experiments. Ligand competition experiments identi®ed the NOEs that originate from the activesite conformation of the inhibitor. Structures were calculated using a combination of distance geometry and restrained energy minimization. The peptide backbone is shown to adopt a reverseturn conformation most closely approximating a type II' b-turn. The resolved conformation of the inhibitor represents a distinctly different structural motif from that determined for Rascompetitive inhibitors. Knowledge of the bound conformation of this novel inhibitor provides a template and future direction for the design of new classes of FPTase antagonists. Abbreviations: FPP, farnesyl diphosphate; FPTase, farnesylprotein transferase; TRNOE, transferred nuclear Overhauser effect.
Excited state intramolecular proton transfer in 2-acetylindan-1,3-dione
Chemical Physics Letters, 1999
The excited-state intramolecular proton transfer (ESIPT) reactions of 2,4-dimethoxy-6-(1-hydroxy-2-naphthyl)-striazine (NTR) and 2,4-dimethoxy-6-(1-hydroxy-2-naphthyl)-1,3-pyrimidine (NPR) were studied by laser photolyses and¯uorescence measurements with the aid of MO calculations. Large Stokes-shifted¯uorescences (D" m 6400 and 7300 cm À1 ) originating from ESIPT were observed for NTR and NPR. Laser photolyses of NTR and NPR gave longlived transients which could be attributed to their trans-keto tautomers ( 1 K tr ) produced by cis±trans isomerization of the proton-transferred cis-keto form ( 1 K Ã cis ) in the S 1 state. Temperature eects on the¯uorescence lifetime and¯uorescence quantum yield of 1 K Ã cis and relative formation yield of 1 K tr showed that another temperature-dependent nonradiative deactivation process competing with the cis±trans isomerization was involved in the relaxation processes of 1 K Ã cis . A lower apparent activation energy (12 kJ mol À1 ) for the total nonradiative deactivation rate of NTR including cis±trans isomerization was obtained in comparison with that (18 kJ mol À1 ) of NPR. Remarkable viscosity eects were observed on the¯uorescence lifetimes of 1 K Ã cis of NTR and NPR at 293 K, indicating that the main deactivation pathway from 1 K Ã cis was the cis±trans isomerization 1 K Ã cis 3 1 K tr . The results of MO calculations on the ground and excited states of NTR and NPR supported a relaxation scheme including ESIPT followed by cis±trans isomerization. Ó