Original Phase 1 Title: Identifying Small Molecule Inhibitors of Hdmx Using Cell-Based Screening Revised Title: Development of a Novel Hdmx Inhibitor for Leukemia
Award last edited on: 6/9/17

Sponsored Program
Awarding Agency
Total Award Amount
Award Phase
Solicitation Topic Code

Principal Investigator
Mukesh Kumar Agarwal

Company Information

Invenio Therapeutics Inc

11000 Cedar Avenue Suite 100
Cleveland, OH 44106
   (216) 789-6000
Location: Single
Congr. District: 11

Phase I

Contract Number: 1R43CA139791-01
Start Date: 4/1/09    Completed: 3/31/11
Phase I year
Phase I Amount
Loss of the p53 signaling pathway, either by mutation or loss of upstream or downstream signaling components, occurs in the vast majority of human cancers. In normal cells, Hdm2 and HdmX coordinately regulate the stability and function of p53. However, each protein is overexpressed in subsets of many different types of human malignancy, leading to inactivation of wild-type p53 function. HdmX overexpression was recently reported to be as high as 20% in breast, colon and lung cancers. Treatment options for tumors harboring wild-type p53 would be greatly expanded if the recent discoveries of low molecular weight compounds capable of disrupting the p53-Hdm2 interaction to induce p53-dependent toxicity continue to show positive results. Preliminary comparison of one small molecule's specificity has shown that HdmX and Hdm2 can be differentially affected, thereby establishing each protein as an independent target for therapy. The goal of this proposal is to develop a new class of small molecules effective against tumor cells retaining wild-type p53 that is transcriptionally repressed due to HdmX overexpression. A cell-based system is proposed that will combine HdmX overexpression with an integrated p53-responsive promoter driving 2- galactosidase expression, an easily measurable and quantifiable specific marker. A screen for compounds that induce p53-dependent transcription will be performed. Candidate compounds that pass through the primary screen will be classified according to their relative strengths and characterized to define the mechanism of p53 activation and the dependence upon HdmX and/or Hdm2 status for efficacy. A limited set of compounds capable of inhibiting HdmX-mediated p53 inactivation will form the basis of a Phase II program aimed at hit-to-lead optimization and the development of prototype therapeutic drugs.

Public Health Relevance:
Cancer cells have acquired genetic alterations that disrupt cellular checkpoints established to limit normal proliferation. In many cancers, these checkpoints are simply suppressed rather than absent, leaving the option to reengage and enforce the hidden limits to proliferation as cancer therapy. We propose to identify compounds that can prevent tumors with a common but specific genetic alteration, namely HdmX protein overexpression, from continuing their aberrant growth.

Public Health Relevance Statement:
Cancer cells have acquired genetic alterations that disrupt cellular checkpoints established to limit normal proliferation. In many cancers, these checkpoints are simply suppressed rather than absent, leaving the option to reengage and enforce the hidden limits to proliferation as cancer therapy. We propose to identify compounds that can prevent tumors with a common but specific genetic alteration, namely HdmX protein overexpression, from continuing their aberrant growth.

Project Terms:
Affect; Apoptosis; Apoptosis Pathway; Apoptotic; Applications Grants; Area; Automobile Driving; Award; Biological; Biology; Blood (Leukemia); Breast; Businesses; Cancer Treatment; Cancer of Lung; Cancers; Cell Communication and Signaling; Cell Culture Techniques; Cell Death, Programmed; Cell Line; Cell Line, Tumor; Cell Lines, Strains; Cell Signaling; CellLine; Cells; Chemicals; Chemistry, Pharmaceutical; Clinical Trials; Clinical Trials, Unspecified; Collaborations; Collection; Colon; Communities; Data; Dependence; Development; Diagnosis; Drivings, Automobile; Drug Evaluation, Preclinical; Drug Kinetics; Drug Screening; Drugs; Ensure; Evaluation Studies, Drug, Pre-Clinical; Evaluation Studies, Drug, Preclinical; Feedback; Future; Galactosidase; Gene Down-Regulation; Gene Transcription; Generalized Growth; Genes, Reporter; Genes, p53; Genetic Alteration; Genetic Change; Genetic Transcription; Genetic defect; Goals; Grant; Grant Proposals; Grants, Applications; Growth; Hdmx protein; High Throughput Assay; Human; Human Resources; Human, General; In Vitro; Intellectual Property; Intracellular Communication and Signaling; Lead; Left; Leukemias, General; Malignant Cell; Malignant Neoplasm Therapy; Malignant Neoplasm Treatment; Malignant Neoplasms; Malignant Tumor; Malignant Tumor of the Lung; Malignant neoplasm of lung; Mammals, Mice; Man (Taxonomy); Man, Modern; Manpower; Measurable; Mediating; Medication; Medicinal Chemistry; Metastasis; Metastasize; Metastatic Neoplasm; Metastatic Tumor; Mice; Molecular Weight; Murine; Mus; Mutation; Neoplasm Metastasis; Normal Cell; Overexpression; Ownership; P53; Paper; Participant; Patients; Pb element; Pharmaceutic Chemistry; Pharmaceutic Preparations; Pharmaceutical Agent; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmaceuticals; Pharmacokinetics; Pharmacologic Substance; Pharmacological Substance; Phase; Preclinical Drug Evaluation; Principal Investigator; Programs (PT); Programs [Publication Type]; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Property; Property, LOINC Axis 2; Protein Overexpression; Proteins; Protocol; Protocols documentation; Publications; Pulmonary Cancer; Pulmonary malignant Neoplasm; RNA Expression; Relative; Relative (related person); Reporter; Reporter Genes; Reporting; Repression; Resistance; SBIR; SBIRS (R43/44); SIS; STTR; Scientific Publication; Screening procedure; Secondary Neoplasm; Secondary Tumor; Series; Signal Transduction; Signal Transduction Systems; Signaling; Sister; Small Business Innovation Research; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Specificity; System; System, LOINC Axis 4; TP53; TP53 gene; TRP53; Testing; Therapeutic; Tissue Growth; Toxic effect; Toxicities; Transcription; Transcription Repression; Transcription, Genetic; Transcriptional Repression; Tumor Cell; Tumor Cell Line; Tumor Cell Migration; Tumor Protein p53 Gene; Validation; Work; angiogenesis; anticancer research; anticancer therapy; base; biological signal transduction; cancer cell; cancer metastasis; cancer research; cancer therapy; career; cell transformation; cell type; clinical investigation; cultured cell line; driving; drug development; drug discovery; drug/agent; experience; gene product; gene repression; genome mutation; heavy metal Pb; heavy metal lead; high throughput screening; in vivo; inhibitor; inhibitor/antagonist; leukemia; lung cancer; malignancy; neoplasm/cancer; neoplastic cell; new approaches; new therapeutics; next generation therapeutics; novel approaches; novel strategies; novel strategy; novel therapeutics; nutlin 3; ontogeny; overexpress; overexpression; p53 Signaling Pathway; personnel; pre-clinical; preclinical; prevent; preventing; programs; prospective; prototype; public health relevance; resistant; screening; screenings; small molecule; success; therapeutic target; transformed cells; tumor; tumor xenograft

Phase II

Contract Number: 2R44CA139791-02A1
Start Date: 4/1/09    Completed: 3/31/17
Phase II year
(last award dollars: 2016)
Phase II Amount

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.

Public Health Relevance Statement:

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.

NIH Spending Category:
Cancer; Hematology; Orphan Drug; Rare Diseases

Project Terms:
Acute; Acute Myelocytic Leukemia; Adverse effects; animal efficacy; Animals; Apoptosis; base; Binding (Molecular Function); Biological Models; Blood; Bone Marrow; cancer cell; cancer therapy; cancer type; Cell Death; cell transformation; Cells; chemotherapy; Clinical; Clinical Research; Clinical Trials; clinically relevant; companion diagnostics; Complex; Development; Disease; DNA Damage; Dose; Drug Kinetics; Exhibits; Future; Goals; Grant; Hematopoietic; Homologous Gene; Human; human disease; Immunodeficient Mouse; In Vitro; inhibitor/antagonist; Killings; Lead; leukemia; Leukemic Cell; Malignant Neoplasms; Modeling; mouse model; Mus; Mutation; Non-Malignant; Normal Cell; novel; Organ; overexpression; Pathway interactions; Patient Selection; Patients; Pharmaceutical Chemistry; Phase; Phase I Clinical Trials; Play; prevent; Property; public health medicine (field); public health relevance; Rattus; Regimen; Reporting; Rodent; Role; Safety; Sampling; screening; small molecule; Specificity; targeted cancer therapy; Testing; Therapeutic; Toxic effect; tumor; Work