Famesylation inhibitors

Peptoids [22] form a particular promising class of oligomeric peptidomimetics, which consists of A-substituted-glycine derivatives. Thus, the concepts to translate a particular peptide sequence, in this case CAAX to a corresponding peptoid sequence is a perfectly suitable approach to obtain potential famesyl inhibitors. This approach was adopted by... 

Dabrah TT, Harwood HL, Huang LG, Jankovich ND, Kaneko T, Li JC, Lindsey S, Moshier PM, Subashi TA, Ther-rien M, Watts PC. CP-225,917 and CP-263,114, Novel Ras Famesylation inhibitors from an unidentified fungus. 1. Taxonomy, fermentation, isolation, and biochemical properties. J. Antibiot. 1997 50 1-7. 

Kohl NE, Conner MW, Gibbs JB, Graham SL, Hartman GD, Oliff A (1995) Development of inhibitors of protein famesylation as potential chemotherapeutic agents. J Cell Biochem Suppl 22 145-150... 

To function, Ras must be attached to the plasma membrane. Translocation from the cytoplasm to membrane requires a series of posttranslational modifications that begin with farnesylation of the cysteine residue, the fourth amino acid residue from the C terminus of the protein, by famesyl protein transferase (FPTase) (64). Attachment of the hydrophobic 15-carbon lipid farnesyl group allows Ras molecule insertion into the plasma membrane and is crucial for Ras signaling activity and transformation properties. As farnesylation is required for oncogenic Ras function, FPTase inhibitors (FTIs) are obvious candidate antineoplastic agents. Several drugs that inhibit Ras farnesylation are at various stages of clinical development (65). 

Nagasu T, Yoshimatsu K, Rowell C, et al. Inhibition of human tumor xenograft growth by treatment with the famesyl transferase inhibitor B956. Cancer Res 1995 55 5310-5314. 

JMC5020>. Imidazole-containing diarylether and diarylsulfone inhibitors of famesyl-protein transferase has been described <99BML3301>. 

Another approach to the management of IM resistance is to combine agents that are individually active against CML but have differing mechanisms of action that may allow either additive or synergistic effects in a non-cross-resistant marmer. This approach has been extensively studied in the literature and will not be reviewed in detail here. An excellent discussion of combination therapy is foimd in the reviews by Hochhaus and La Rosee (52,85). Some combination approaches have utilized famesyl transferase inhibition such as lonafamib in combination with IM, inhibitors of the mammalian target of rapamycin (mTOR) in combination with IM and combining mycophenolic acid, an inhibitor of the JAK-STAT pathway. 

An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide scaffold- and nonpeptide template-based approaches is that for the Ras famesyl transferase inhibitor discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis [81]. Substrate sequences for famesyl transferase have the consensus Cy s-A A, - A A2-Met motif (AA refers to Val or lie). Both substrate-based... 

Singh SB, Ball RG, Bills GF, Cascales C, Gibbs JB, Goetz MA, Hoogsteen K, Jenkins RG, Liesch JM, Lingham RB, Silverman KC, Zink DL (1996) Chemistry and Biology of Cylindrols Novel Inhibitors of Ras Famesyl-Protein Transferase from Cylindrocarpon lucidum. J Org Chem 61 7727... 

Gamer, R. C., Goris, I., Laenen, A. A., Vanhoutte, E., Meuldermans, W., Gregory, S., Gamer, J. V., Leong, D., Whattam, M., Calam, A., and Snel, C. A. (2002). Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study—Experience with 14C-labeled (R)-6-[amino(4-chlorophenyl)(l-methyl-l //-imidazol-5-yl)methyl -4-(3-chlorophenyl)- l-methyl-2(17/ i-quinolinone (R115777), a famesyl transferase inhibitor. Drug Metab. Dispos. 30 823-830. 

Mo4 is believed to act as an inhibitor of famesylation of the ras oncogene. In addition, it is thought to interfere with the first steps in isoprenylation of hydroxymethylglutarate [35]. In contrast, Mo4 has been reported to lack chemoprevention effects in a rat multiorgan carcinogenesis model [57]. 

Addition of the terpene, famesol, to cysteine residues near the end of protein chains is a cmcial process for transporting some proteins to the intended membrane compartment. This process thus plays an important role in cell proliferation. Inhibitors of the enzyme that catalyzes farnesyla-tion, famesyl transferase, provide yet one more mechanism for interrupting the multiplication of malignant cells. One of several synthesis of this agent... 

Parallel liquid synthesis has been applied to the synthesis of a range of N,N -disubstituted 3-aminoazepin-2-ones 7 (e.g. R = w-BrC6H4) starting from 6. These compounds were required for SAR studies as specific famesyl transferase inhibitors <03BMC3193>. 

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