Discovery of allele-selective KRAS inhibitors

描述（由申请人提供）：有推测认为小的GTPases可以作为多种癌症类型的有效治疗靶点。例如，有可能通过使用小分子KRAS抑制剂来抵消KRAS突变对胰腺癌的影响；然而，Kras在小鼠体内的本质表明，这些抑制剂可能存在基于机制的毒性。验证小gtpase的治疗指数对于确定新的药物靶点和了解特定癌症的致病机制至关重要。然而，小gtpase是具有挑战性的药物靶标（尽管不一定不可能靶向），如果它们没有在疾病模型中得到验证，那么就没有动力在这些困难的靶标上花费大量资源。我们的目标是通过开发一个可扩展的系统来测试小gtpase药理抑制的体外和体内后果来解决这个问题。我们的长期目标是确定小gtpase是否是特定疾病的有效治疗靶点。作为实现这个目标的第一步，

DESCRIPTION (provided by applicant): There is speculation that small GTPases could serve as effective therapeutic targets in multiple cancer types. For example, it may be possible to counteract the effects of KRAS mutations in pancreatic cancers by using a small molecule KRAS inhibitor; however the essential nature of Kras in mice suggests there may be mechanism-based toxicity to such inhibitors. Validating the therapeutic index of small GTPases is critical for identifying new drug targets and for understanding pathogenic mechanisms of specific cancers. However, small GTPases are challenging drug targets (although not necessarily impossible to target) there is less incentive to spend significant resources on such difficult targets if they have not been validated in disease models. We aim to address this issue by developing a scalable system for testing the in vitro and in vivo consequences of pharmacological inhibition of small GTPases. Our long-term goal is to determine whether small GTPases are effective therapeutic targets for specific diseases. As a first step towards this goal, we are focused on developing a set of tools that would enable us to determine whether pharmacological inhibition of KRAS has limited toxicity in mice. We propose to design small molecules that are capable of inhibiting an engineered mutant allele of KRAS. These allele-selective inhibitors will be designed to have ADME/PK suitable for use in animal models. If successful, this system could be extended to test the therapeutic benefit of pharmacological inhibition of other small GTPases. Ultimately, these results would determine which small GTPases serve as effective drug targets.