DESIGN OF RAS ONCOPROTEIN INHIBITORS

ras原癌基因的致癌突变在大多数肿瘤中发现有20%。 人类癌症的类型和超过50%的结肠和胰腺癌 癌近年来，研究了ras在其细胞内的三维结构， “活性”和“非活性”构象状态已通过X射线 衍射法 在这里，我们提出了基于结构的，计算机辅助的战略 用于设计RAS抑制剂用作治疗剂， 癌症的治疗。该战略的第一阶段将设计 在一个更大的候选配体小组（>50种化合物）中， 其中有希望的将被合成和评估（生物学上 和通过X射线衍射）在相II中。第二和第三阶段将涉及 进一步的设计、合成和测试。

Oncogenic mutations of the ras protooncogene are found in 20% of most types of human cancer and greater than 50% of colon and pancreatic carcinomas. Recently, the three-dimensional structures of ras in its "active" and "inactive" conformational states have been solved by X-ray diffraction. Here we propose structure based, computer-aided strategy for the design of ras inhibitors for use as therapeutic agents in the treatment of cancer. Phase I of this strategy will result in the design of a larger panel (>50 compounds) of candidate ligands, the most promising of which will be synthesized and evaluated (both biologically and by X-ray diffraction) in phase II. Phase II and III will involve further rounds of design, synthesis and testing.