Nord L D, Martin D S
Catholic Medical Center, Department of Cancer Research, Woodheaven, NY 11421.
Curr Opin Oncol. 1993 Nov;5(6):1017-22. doi: 10.1097/00001622-199311000-00012.
Molecular modeling techniques and a knowledge of thymidylate synthase protein structure have assisted in the development of several potent new inhibitors of thymidylate synthase, the enzyme mediating de novo formation of thymidylate for use in DNA synthesis. Information on several new and specific thymidylate synthase inhibitors, including ICI-D1694, 1843U89, AG-331, and AG-337, is presented. The effects of thymidylate synthase inhibition on the induction of thymidylate synthase protein synthesis have raised the question of whether thymidylate synthase inhibition alone will be sufficient to provide a desirable clinical effect. Formation of a thymidylate synthase-inhibitor complex prevents posttranscriptional regulation of thymidylate synthase synthesis, allowing for increased thymidylate synthase synthesis and the possibility of drug resistance. Therefore, recent efforts have also focused on characterizing this increase in thymidylate synthase protein induced by inhibitors of thymidylate synthase and on devising combination drug strategies that may prevent the induction of thymidylate synthase protein synthesis in addition to inhibiting thymidylate synthase activity.
分子建模技术以及胸苷酸合成酶蛋白质结构的相关知识，助力了几种强效新型胸苷酸合成酶抑制剂的研发。胸苷酸合成酶是一种介导用于DNA合成的胸苷酸从头合成的酶。本文介绍了几种新型特异性胸苷酸合成酶抑制剂的信息，包括ICI-D1694、1843U89、AG-331和AG-337。胸苷酸合成酶抑制对胸苷酸合成酶蛋白质合成诱导的影响，引发了仅靠胸苷酸合成酶抑制是否足以产生理想临床效果的问题。胸苷酸合成酶-抑制剂复合物的形成会阻止胸苷酸合成酶合成的转录后调控，从而导致胸苷酸合成酶合成增加以及产生耐药性的可能性。因此，近期的研究工作也集中在表征由胸苷酸合成酶抑制剂诱导的胸苷酸合成酶蛋白质的这种增加，以及设计联合用药策略，这些策略除了抑制胸苷酸合成酶活性外，还可能防止胸苷酸合成酶蛋白质合成的诱导。
