Discovery of RRx-001, a Myc and CD47 Downregulating Small Molecule with Tumor Targeted Cytotoxicity and Healthy Tissue Cytoprotective Properties in Clinical Development

J Med Chem. 2021 Jun 10;64(11):7261-7271. doi: 10.1021/acs.jmedchem.1c00599. Epub 2021 May 27.

Abstract

After extensive screening of aerospace compounds in an effort to source a novel anticancer agent, RRx-001, a first-in-class dinitroazetidine small molecule, was selected for advancement into preclinical and clinical development. RRx-001 is a minimally toxic small molecule with a distinct chemical structure and mechanism of action. The paradox of RRx-001 is that it mediates both antitumor cytotoxicity and normal tissue protection. The question of exactly how RRx-001 does this, and by means of what mechanism(s), depending on the route of delivery, intravenous or intratumoral, are explored. RRx-001 is currently in phase 2 and 3 clinical trials for the treatment of multiple solid tumor malignancies and as a supportive care drug.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Azetidines / chemistry*
  • Azetidines / pharmacology
  • Azetidines / therapeutic use
  • CD47 Antigen / genetics
  • CD47 Antigen / metabolism*
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Down-Regulation / drug effects
  • Half-Life
  • Humans
  • Immunogenic Cell Death / drug effects
  • Male
  • Mice
  • Mice, Inbred C3H
  • Neoplasms / diagnostic imaging
  • Neoplasms / drug therapy
  • Nitro Compounds / chemistry*
  • Nitro Compounds / pharmacology
  • Nitro Compounds / therapeutic use
  • Positron-Emission Tomography
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Structure-Activity Relationship
  • Transplantation, Heterologous
  • Tumor-Associated Macrophages / cytology
  • Tumor-Associated Macrophages / drug effects
  • Tumor-Associated Macrophages / metabolism

Substances

  • Antineoplastic Agents
  • Azetidines
  • CD47 Antigen
  • CD47 protein, human
  • Nitro Compounds
  • Proto-Oncogene Proteins c-myc
  • RRx-001