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（由适用提供）：尽管癌症治疗方面取得了进步，但大多数使用的癌症治疗仍然出色的显着毒性并诱导DNA损伤。 DNA损伤虽然对非恶性细胞有毒，但通常在通过p53诱导杀死癌细胞中起着重要作用。最近，为了开发毒性较小，靶向较高的癌症疗法，已经提出了诱发p53的替代策略。一种策略涉及破坏p53与其负调节器HDMX和/或HDM2的相互作用。在我们的第一阶段赠款中，我们确定了一种新型的HDMX/p53的小分子抑制剂CTX1，可以破坏HDMX/p53的相互作用，并以非DNA损伤方式导致p53诱导和癌细胞死亡。 CTX1可以直接与HDMX相互作用，并优先杀死表达p53的癌细胞。如预期的那样，通过并发的HDM2抑制，CTX1的活性得到了增强。尽管如此，该化合物即使在循环原代人AML的小鼠模型中也表现出有希望的活性。该提案的目的是开发我们在第一阶段授予临床试验中确定的HDMX抑制剂的优化版本。该提案的目的是通过小鼠效率，药代动力学和毒性研究来评估该药物的临床潜力。希望这项工作将导致研究的倡议和1期临床试验的主动性。