Abstract
Among the newer and promising weapons against cancer are Farnesyl Transferase Inhibitors (FTI). Indeed it is known that the enzyme Farnesyl Transferase (FT), catalyses the prenylation of cysteine residues of several proteins associated with cancer progression, including oncogenic forms of Ras.FTI could alter tumour progression. Exploration of our corporate structural database, based on concepts of diversity and similarity, brought forward a quinazoline-2,4-dione possessing weak farnesyl transferase inhibitory properties. A systematic modulation of structural parameters allowed the elaboration of a series of analogs out of which the most potent compound (21b) exhibited an IC50 of 19 nM on FT, an excellent cellular activity on the oncogenic H-Ras-transfected cell line Ras , as well as selectivity (ratio of IC50 on parental RAT2 cells/ IC50 on Ras cells > 2000). Moreover this compound also showed encouraging “in vivo” activity. The synthesis of these new chemical entities as well as the structure activity relationships found following pharmacological testing, is described.
Keywords: Database mining, farnesyl transferase, farnesyl transferase inhibitors, quinazoline-2,4-diones, structure activity
Medicinal Chemistry
Title: Controlled Exploration of Structural Databases: The Case of Farnesyl Transferase Inhibitors
Volume: 5 Issue: 3
Author(s): A. Tizot, G. C. Tucker, A. Pierre, J. Hickman and S. Goldstein
Affiliation:
Keywords: Database mining, farnesyl transferase, farnesyl transferase inhibitors, quinazoline-2,4-diones, structure activity
Abstract: Among the newer and promising weapons against cancer are Farnesyl Transferase Inhibitors (FTI). Indeed it is known that the enzyme Farnesyl Transferase (FT), catalyses the prenylation of cysteine residues of several proteins associated with cancer progression, including oncogenic forms of Ras.FTI could alter tumour progression. Exploration of our corporate structural database, based on concepts of diversity and similarity, brought forward a quinazoline-2,4-dione possessing weak farnesyl transferase inhibitory properties. A systematic modulation of structural parameters allowed the elaboration of a series of analogs out of which the most potent compound (21b) exhibited an IC50 of 19 nM on FT, an excellent cellular activity on the oncogenic H-Ras-transfected cell line Ras , as well as selectivity (ratio of IC50 on parental RAT2 cells/ IC50 on Ras cells > 2000). Moreover this compound also showed encouraging “in vivo” activity. The synthesis of these new chemical entities as well as the structure activity relationships found following pharmacological testing, is described.
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Cite this article as:
Tizot A., Tucker C. G., Pierre A., Hickman J. and Goldstein S., Controlled Exploration of Structural Databases: The Case of Farnesyl Transferase Inhibitors, Medicinal Chemistry 2009; 5 (3) . https://dx.doi.org/10.2174/157340609788185891
DOI https://dx.doi.org/10.2174/157340609788185891 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
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Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
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