Discovery of allele-selective KRAS inhibitors

描述(由申请人提供)：有猜测认为小的GTP酶可以作为多种癌症类型的有效治疗靶点。例如，可以通过使用小分子KRAS抑制剂来抵消胰腺癌中KRAS突变的影响；然而，Kras在小鼠身上的本质表明，这种抑制剂可能存在基于机制的毒性。验证小GTP酶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，小的GTP酶正在挑战药物靶标(尽管不一定不可能靶标)如果这些靶标没有在疾病模型中得到验证，那么在这些困难的靶标上花费大量资源的动机就会减少。我们的目标是通过开发一种可扩展的系统来解决这个问题，该系统用于测试小GTP酶药物抑制的体外和体内后果。我们的长期目标是确定小的GTP酶是否是治疗特定疾病的有效靶点。作为迈向这一目标的第一步， 我们专注于开发一套工具，使我们能够确定KRAS的药理抑制是否对小鼠具有有限的毒性。我们建议设计能够抑制KRAS的工程突变等位基因的小分子。这些等位基因选择性抑制剂将被设计成具有ADME/PK，适合在动物模型中使用。如果成功，这个系统可以扩展到测试其他小的GTP酶的药物抑制的治疗益处。最终，这些结果将决定哪些小的GTP酶作为有效的药物靶点。

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.