Discovery of MD-224 as a First-in-Class, Highly Potent, and Efficacious Proteolysis Targeting Chimera Murine Double Minute 2 Degrader Capable of Achieving Complete and Durable Tumor Regression

J Med Chem. 2019 Jan 24;62(2):448-466. doi: 10.1021/acs.jmedchem.8b00909. Epub 2018 Dec 10.


Human murine double minute 2 (MDM2) protein is a primary endogenous cellular inhibitor of the tumor suppressor p53 and has been pursued as an attractive cancer therapeutic target. Several potent, nonpeptide, small-molecule inhibitors of MDM2 are currently in clinical development. In this paper, we report our design, synthesis, and evaluation of small-molecule MDM2 degraders based on the proteolysis targeting chimera (PROTAC) concept. The most promising compound (MD-224) effectively induces rapid degradation of MDM2 at concentrations <1 nM in human leukemia cells. It achieves an IC50 value of 1.5 nM in inhibition of growth of RS4;11 cells and also low nanomolar IC50 values in a panel of leukemia cell lines. MD-224 achieves complete and durable tumor regression in vivo in the RS4;11 xenograft tumor model in mice at well-tolerated dose schedules. MD-224 is thus a highly potent and efficacious MDM2 degrader and warrants extensive evaluations as a new class of anticancer agent.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Design
  • Humans
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Leukemia / drug therapy
  • Leukemia / pathology
  • Mice
  • Proteolysis*
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-mdm2 / genetics
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Spiro Compounds / pharmacology
  • Spiro Compounds / therapeutic use
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Xenograft Model Antitumor Assays


  • 4-(6''-chloro-4'-(3-chloro-2-fluorophenyl)-2''-oxodispiro(cyclohexane-1,2'-pyrrolidine-3',3''-indoline)-5'-carboxamido)benzoic acid
  • Apoptosis Regulatory Proteins
  • BBC3 protein, human
  • Indoles
  • Proto-Oncogene Proteins
  • Spiro Compounds
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2