KRas Ligand Development

 描述(由申请人提供)：靶向RAS癌基因是国家癌症研究所的优先事项，因为它们是最重要的人类癌症驱动因素。事实上，RAS基因突变约占所有癌症的30%，包括大部分结直肠癌、肺癌和大多数胰腺癌。因此，从治疗上解决突变RAS的能力将对癌症死亡率产生重大影响。几十年来，人们一直认识到最常见的突变型RAS，KRAS的重要性，但由于开发KRAS抑制剂的困难，目前还没有FDA批准的有效针对这种癌基因的治疗方法。然而，对GDP与GTP结合的KRAS结构的电子构象分析表明，潜在的配体口袋只存在于GTP结合的结构中。在这里，我们建议使用结构导向的小分子设计策略来开发对GTP结合的构象口袋具有高亲和力和选择性的配体。一旦设计、合成和表征，这些配体将作为KRAS的招募部分，在未来的KRAS靶向蛋白水解靶向嵌合体(PROTACs)，这是我的实验室开发的一项技术，将特定靶向的蛋白质定向到泛素-蛋白酶体系统，以有效地破坏它们。通过最终开发新的KRAS降解分子，我们的目标是使KRAS在药物上变得脆弱。

 DESCRIPTION (provided by applicant): Targeting RAS oncogenes is a priority for the National Cancer Institute since they are the foremost human cancer drivers. In fact, mutations in RAS contribute to approximately 30% of all cancers, including large fractions of colorectal carcinoma, lung carcinoma, and most pancreatic carcinoma. Hence, the ability to therapeutically address mutant RAS would have a significant impact on cancer mortality. The importance of the most commonly found mutant RAS, KRAS has been appreciated for decades but despite much effort, there are no FDA-approved therapies that effectively target this oncogene due to the difficulty of developing KRas inhibitors. However, an in silico conformational analysis of the GDP- vs. GTP-bound KRas structures revealed a potential ligand pocket that is only present in the GTP-bound structure. Here, we propose to use a structure-guided small molecule design strategy to develop ligands that are high affinity and selective for that GTP-bound conformational pocket. Once designed, synthesized and characterized, these ligands will serve as KRas recruiting moieties in future KRas-targeting Proteolysis Targeting Chimerae (PROTACs), a technology developed in my lab that directs specifically-targeted proteins to the ubiquitin-proteasome system for their efficacious destruction. By ultimately developing novel KRas degrading molecules, we aim to make KRas pharmaceutically vulnerable.