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

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 p Recently in order to develop less toxic and more targeted cancer therapies alternative strategies to induce p have been proposed One strategy involves disrupting p interactions with its negative regulators HdmX and or Hdm In our phase grant we identified CTX a novel small molecule inhibitor of HdmX p that can disrupt HdmX p interactions and lead to p induction and cancer cell death in a non DNA damage dependent fashion CTX can directly interact with HdmX and preferentially kill cancer cells expressing p As expected the activity of CTX is enhanced by concurrent Hdm 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 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 clinical trial PUBLIC HEALTH RELEVANCE This project is highly relevant to public health as its main objective is to lead to the development of novel therapies for patients with Acute Myeloid Leukemia that are both efficacious and have low toxicity As the current AML therapeutics have low efficacy and high toxicities there is a significant need for new therapies