Original Phase 1 Title: Identifying Small Molecule Inhibitors of HdmX using Cell-based Screening Revised Title: Development of a Novel HdmX Inhibitor for Leukemia

 描述(申请人提供)：尽管癌症治疗取得了进展，但大多数正在使用的癌症治疗药物仍然表现出显著的毒性并导致DNA损伤。DNA损伤虽然对非恶性细胞有毒性，但通常在通过诱导p53杀死癌细胞方面发挥重要作用。最近，为了开发毒性更低、靶向性更强的癌症治疗方法，人们提出了诱导p53基因表达的替代策略。一种策略涉及干扰P53与其负调控因子HdmX和/或Hdm2的相互作用。在我们的第一阶段资助中，我们确定了CTX1，一种新型的HdmX/P53小分子抑制物，可以破坏HdmX/P53的相互作用，并以非DNA损伤依赖的方式导致P53诱导和癌细胞死亡。CTX1可直接与HdmX相互作用，优先杀伤表达P53的癌细胞。正如预期的那样，同时抑制Hdm2可以增强CTX1的活性。尽管如此，该化合物在循环原发人类AML的小鼠模型中仍显示出良好的活性，即使作为单一药物也是如此。这项建议的目标是开发我们的HdmX抑制剂的优化版本，我们在临床试验的第一阶段拨款中确定了这一版本。这项建议的目的是通过小鼠疗效、药代动力学和毒性研究来评估该制剂的临床潜力。希望这项工作将导致启动IND使能研究和启动1期临床试验。

 DESCRIPTION (provided by applicant): Despite advances in cancer therapy, the majority of cancer therapeutics in use still exhibit significant toxicity and induce DNA damage. The DNA damage, though toxic to non-malignant cells, often plays an important role in killing cancer cells through the induction of p53. Recently, in order to develop less toxic and more targeted cancer therapies, alternative strategies to induce p53 have been proposed. One strategy involves disrupting p53 interactions with its negative regulators, HdmX and/or Hdm2. In our phase 1 grant we identified, CTX1, a novel small molecule inhibitor of HdmX/p53 that can disrupt HdmX/p53 interactions and lead to p53 induction and cancer cell death in a non-DNA damage dependent fashion. CTX1 can directly interact with HdmX and preferentially kill cancer cells expressing p53. As expected, the activity of CTX1 is enhanced by concurrent Hdm2 inhibition. Nonetheless, this compound demonstrates promising activity even as a single agent in a mouse model of circulating primary human AML. The goal of this proposal is to develop an optimized version of our HdmX inhibitor that we identified during our phase 1 grant towards clinical trials. The aims of this proposal are to assess the clinical potential of this agent through mouse efficacy, pharmacokinetic and toxicity studies. It is hoped that this work will lead to the initiaton of IND-enabling studies and the initiation of a phase 1 clinical trial.