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

最初的 1 期标题：使用基于细胞的筛选识别 HdmX 的小分子抑制剂修订后的标题：开发用于白血病的新型 HdmX 抑制剂

• 批准号: 9053452
• 负责人: Mukesh Kumar Agarwal
• 金额: $ 71.78万
• 依托单位: MIRX PHARMACEUTICALS, LTD
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9053452
• 关键词: Acute Myelocytic Leukemia; Adverse effects; Animals; Apoptosis; Binding; Biological Models; Blood; Bone Marrow; Cell Death; Cells; Clinical; Clinical Research; Clinical Trials; Complex; DNA Damage; Development; Disease; Dose; Drug Kinetics; Exhibits; Future; Goals; Grant; Health; Hematopoietic; Homologous Gene; Human; Immunodeficient Mouse; In Vitro; Lead; Leukemic Cell; Malignant Neoplasms; Modeling; Mus; Mutation; Non-Malignant; Normal Cell; Organ; Pathway interactions; Patient Selection; Patients; Pharmaceutical Chemistry; Phase; Phase I Clinical Trials; Play; Property; Public Health; Rattus; Regimen; Reporting; Rodent; Role; Safety; Sampling; Specificity; TP53 gene; Testing; Therapeutic; Toxic effect; Work; acute toxicity; animal efficacy; base; cancer cell; cancer therapy; cancer type; cell transformation; chemotherapy; clinically relevant; companion diagnostics; human disease; inhibitor/antagonist; killings; leukemia; mouse model; mutational status; novel; novel therapeutics; overexpression; prevent; screening; small molecule inhibitor; targeted cancer therapy; tumor

 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.

 描述（由申请人提供）：尽管癌症治疗取得了进展，但大多数使用的癌症治疗剂仍然表现出显着的毒性并诱导DNA损伤。DNA损伤虽然对非恶性细胞有毒，但通常在杀死癌细胞方面发挥重要作用。最近，为了开发毒性较小且更具针对性的癌症疗法，已经提出了诱导 p53 的替代策略，其中一种策略涉及破坏 p53 与其负调节因子 HdmX 和/或的相互作用。 Hdm2。在我们的第一阶段资助中，我们发现了 CTX1，一种新型的 HdmX/p53 小分子抑制剂，它可以破坏 HdmX/p53 相互作用，并以非 DNA 损伤依赖性方式导致 p53 诱导和癌细胞死亡。正如预期的那样，CTX1 的活性通过同时抑制 Hdm2 得到增强，尽管如此，该化合物即使作为单一化合物也表现出良好的活性。该提案的目标是开发我们在临床试验第一阶段拨款中确定的 HdmX 抑制剂的优化版本。该提案的目的是评估该药物的临床潜力。通过小鼠功效、药代动力学和毒性研究，希望这项工作能够启动 IND 研究并启动 1 期临床试验。