James G L, Goldstein J L, Brown M S, Rawson T E, Somers T C, McDowell R S, Crowley C W, Lucas B K, Levinson A D, Marsters J C
Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas 75235.
Science. 1993 Jun 25;260(5116):1937-42. doi: 10.1126/science.8316834.
Oncogenic Ras proteins transform animal cells to a malignant phenotype only when modified by farnesyl residues attached to cysteines near their carboxyl termini. The farnesyltransferase that catalyzes this reaction recognizes tetrapeptides of the sequence CAAX, where C is cysteine, A is an aliphatic amino acid, and X is a carboxyl-terminal methionine or serine. Replacement of the two aliphatic residues with a benzodiazepine-based mimic of a peptide turn generated potent inhibitors of farnesyltransferase [50 percent inhibitory concentration (IC50) < 1 nM]. Unlike tetrapeptides, the benzodiazepine peptidomimetics enter cells and block attachment of farnesyl to Ras, nuclear lamins, and several other proteins. At micromolar concentrations, these inhibitors restored a normal growth pattern to Ras-transformed cells. The benzodiazepine peptidomimetics may be useful in the design of treatments for tumors in which oncogenic Ras proteins contribute to abnormal growth, such as that of the colon, lung, and pancreas.
致癌性Ras蛋白只有在其羧基末端附近的半胱氨酸被法尼基残基修饰时，才会将动物细胞转化为恶性表型。催化此反应的法尼基转移酶识别序列为CAAX的四肽，其中C为半胱氨酸，A为脂肪族氨基酸，X为羧基末端的甲硫氨酸或丝氨酸。用基于苯并二氮杂䓬的肽转角模拟物取代两个脂肪族残基，可产生强效的法尼基转移酶抑制剂[半数抑制浓度（IC50）<1 nM]。与四肽不同，苯并二氮杂䓬肽模拟物可进入细胞，并阻断法尼基与Ras、核纤层蛋白及其他几种蛋白质的结合。在微摩尔浓度下，这些抑制剂可使Ras转化细胞恢复正常生长模式。苯并二氮杂䓬肽模拟物可能有助于设计针对致癌性Ras蛋白导致异常生长的肿瘤（如结肠癌、肺癌和胰腺癌）的治疗方法。
