Scholten J D, Zimmerman K, Oxender M, Sebolt-Leopold J, Gowan R, Leonard D, Hupe D J
Department of Biochemistry, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Bioorg Med Chem. 1996 Sep;4(9):1537-43. doi: 10.1016/0968-0896(96)00146-0.
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 how a prenyl group is enzymatically 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.
蛋白质转移酶（FPTase）抑制剂的关注，使人们对这种蛋白质的酶学有了更深入的了解。由于对异戊二烯基如何通过酶促转移到肽硫醇上有了更深入的认识，合理设计的异戊二烯基转移抑制剂已成为潜在的新药候选物。本文将探讨我们对FPTase介导的催化作用的理解进展如何影响作为潜在癌症治疗药物的FPTase抑制剂的设计。在没有该酶的结构信息的情况下，底物类似物构成了药物设计的第一个领域：这些包括rasP21四个C末端氨基酸的拟肽以及法尼基二磷酸类似物。此外，发现磷酸根阴离子可增强某些已知对法尼基二磷酸具有竞争性的化合物的抑制效力，因此引入磷酸根阴离子也可能为改进抑制剂设计提供基础。
