Abstract
Therapeutic interest in farnesyltransferase inhibitors (FTIs) historically grew out of a desire to target the ras oncogene. Roughly 30% of all human tumors possess a mutation in one of the ras proto-oncogenes. These mutations result in guanosine triphosphate (GTP) becoming permanently bound to Ras, resulting in uncontrolled cellular proliferation. Some tumor types, namely pancreatic and colon cancers, are especially refractory to conventional chemotherapy and exhibit a particularly high incidence of activating ras mutations (approx 90 and 50%, respectively). Interest in farnesyltransferase (FTase) arose because this enzyme represented a potential target for interfering with Ras function. Ras must be anchored to the plasma membrane to act as a transducer of signaling events. Because it has no transmembrane domain, Ras is post-translationally modifed by FTase, thereby acquiring a farnesyl group and consequently the requisite hydrophobicity for membrane attachment. The rationale for FTase as an anticancer drug target has been comprehensively reviewed elsewhere (1–3).
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Sebolt-Leopold JS. A case for ras targeted agents as antineoplastics, in: Cancer Therapeutics: Experimental and Clinical Agents ( Teicher B, ed.), Humana Press, Totowa, NJ, 1995, pp. 395–415.
Leonard DM. Ras farnesyltransferase: a new therapeutic target. J Med Chem 1997; 40: 2971–2990.
Cox AD, Der CJ. Farnesyltransferase inhibitors and cancer treatment: targeting simply Ras? Biochim Biophys Acta 1997; 1333: F51–F71.
Venet M, Angibarud P, Sanz G, Poignet H, End D, Bowden C. Synthesis and in-vitro structure-activity relationships of imidazolyl-2-quinolinones as farnesyl protein transferase inhibitors (FTI). Proc Amer Assoc Cancer Res 1998; 39: 318.
James GL, Goldstein JL, Brown MS. Polylysine and CVIM sequences of KrasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 1995; 270: 6221–5226.
Sun J, Qian Y, Hamilton AD, Sebti SM. Ras CAAX peptidomimetic FTI 276 selectively blocks tumour growth in nude mice of a human lung carcinoma with k-ras mutation and p53 deletion. Cancer Res 1995; 55: 4243–4247.
Kohl NE, Omer CA, Conner MW, Anthony NJ, Davide JP, Desolms SJ, et al. Inhibition of farnesyltransferase induces regresssion of mammary and salivary carcinomas in ras transgenic mice. Nature Med 1995; 1: 792–797.
Goldstein JL, Brown MS, Stradley SJ, Reiss Y, Gierasch LM. Nonfarnesylated tetrapeptide inhibitors of protein farnesyltransferase. J Biol Chem 1991; 266:15, 575–15, 578.
Leonard DM, Shuler KR, Poulter CJ, Eaton SR, Sawyer TK, Hodges JC, et al. Structure-activity relationships of cysteine-lacking pentapeptide derivatives that inhibit ras farnesyltransferase. J Med Chem 1997; 40: 192–200.
Scholten JD, Zimmerman K, Oxender GM, Sebolt-Leopold JS, Gowan R, Leonard D, Hupe DJ. Inhibitors of farnesyl:protein transferase—a possible cancer chemotherapeutic. Bioorg Med Chem 1996; 4: 1537–1543.
Scholten JD, Zimmerman KK, Oxender MG, Leonard D, Sebolt-Leopold J, Gowan R, Hupe DJ. Synergy between anions and farnesyldiphosphate competitive inhibitors of farnesyl:protein transferase. J Biol Chem 1997; 272:18, 077–18, 081.
Hudspeth JP, Kaltenbronn JS, Repine JT, Roark WH, Stier MA. U.S. Patent No. 4,735, 933, 1988.
McNamara DJ, Dobrusin E, Leonard DM, Shuler KR, Kaltenbronn, JS, Quin J III, et al. C-Terminal modifications of histidyl-N-benzylglycinamides to give improved inhibition of ras farnesyltransferase, cellular activity, anticancer activity in mice. J Med Chem 1997; 40: 3319–3322.
Moasser MM, Sepp-Lorenzino L, Kohl NE, Oliff A, Balog A, Su DS, et al. Farnesyl transferase inhibitors cause enhanced mitotic sensitivity to taxol and epothilones. Proc Natl Acad Sci USA 1998; 95: 1369–1374.
Bernhard EJ, Kao G, Cox AD, Sebti SM, Hamilton AD, Muschel RJ, McKenna WG. The farnesyltransferase inhibitor FTI-277 radiosensitizes H-ras-transformed rat embryo fibroblasts. Cancer Res 1996; 56: 1727–1730.
Williams TM, Ciccarone TM, MacTough SC, Bock RL, Conner MW, Davide JP, et al. 2-Substituted piperazines as constrained amino acids. Application to the synthesis of potent, non carboxylic acid inhibitors of farnesyltransferase. J Med Chem 1996; 39: 1345–1348.
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2001 Springer Science+Business Media New York
About this chapter
Cite this chapter
Sebolt-Leopold, J.S., Leonard, D.M., Leopold, W.R. (2001). Histidylbenzylglycinamides. In: Sebti, S.M., Hamilton, A.D. (eds) Farnesyltransferase Inhibitors in Cancer Therapy. Cancer Drug Discovery and Development. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-59259-013-1_8
Download citation
DOI: https://doi.org/10.1007/978-1-59259-013-1_8
Publisher Name: Humana Press, Totowa, NJ
Print ISBN: 978-1-4684-9606-2
Online ISBN: 978-1-59259-013-1
eBook Packages: Springer Book Archive