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，但使用中的大多数癌症治疗剂仍表现出显著的毒性并诱导DNA损伤。DNA损伤虽然对非恶性细胞有毒，但通常通过诱导p53在杀死癌细胞中起重要作用。最近，为了开发毒性更小和更具靶向的癌症疗法，已经提出了诱导p53的替代策略。一种策略涉及破坏p53与其负调控因子HdmX和/或Hdm 2的相互作用。在我们的1期研究中，我们鉴定了CTX 1，一种新型的HdmX/p53小分子抑制剂，可以破坏HdmX/p53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。CTX 1可以直接与HdmX相互作用，并优先杀死表达p53的癌细胞。正如预期的那样，CTX 1的活性通过同时抑制Hdm 2而增强。尽管如此，该化合物在循环原发性人AML的小鼠模型中即使作为单一药剂也显示出有希望的活性。该提案的目标是开发一种优化版本的HdmX抑制剂，该抑制剂是我们在临床试验的第一阶段拨款中确定的。本提案的目的是通过小鼠疗效、药代动力学和毒性研究评估该药物的临床潜力。希望这项工作能够启动IND支持研究并启动1期临床试验。