Discovery of allele-selective KRAS inhibitors

描述（由申请人提供）：推测小GTP酶可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，小鼠中Kras的基本性质表明，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理解特定癌症的致病机制至关重要。然而，小GTP酶是具有挑战性的药物靶标（尽管不一定不可能靶向），如果它们尚未在疾病模型中得到验证，则将大量资源花费在这些困难的靶标上的动机较小。我们的目标是解决这个问题，通过开发一个可扩展的系统，用于测试在体外和体内的小GTP酶的药理学抑制的后果。我们的长期目标是确定小GTP酶是否是特定疾病的有效治疗靶点。作为实现这一目标的第一步， 我们专注于开发一套工具，使我们能够确定KRAS的药理学抑制是否在小鼠中具有有限的毒性。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为具有适用于动物模型的ADME/PK。如果成功，该系统可以扩展到测试其他小GTP酶的药理学抑制的治疗益处。最终，这些结果将决定哪些小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.