Discovery of a clinical stage multi-kinase inhibitor sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na): synthesis, structure-activity relationship, and biological activity

J Med Chem. 2011 Sep 22;54(18):6254-76. doi: 10.1021/jm200570p. Epub 2011 Aug 17.


Cyclin D proteins are elevated in many cancer cells, and targeted deletion of cyclin D1 gene in the mammary tissues protects mice from breast cancer. Accordingly, there is an increasing awareness of this novel nonenzymatic target for cancer therapeutics. We have developed novel, nonalkylating styrylbenzylsulfones that induce cell death in wide variety of cancer cells without affecting the proliferation and survival of normal cells. The development of derivatized styrylbenzylsulfones followed logically from a tumor cell cytotoxicity screen performed in our laboratory that did not have an a priori target profile. Modifications of some of the precursor molecules led to lead optimization with regard to tumor cell cytotoxicity. In this report we describe the synthesis and structure-activity relationships of novel, nonalkylating (E)-styrylbenzylsulfones and the development of the novel anticancer agent sodium (E)-2-{2-methoxy-5-[(2',4',6'-trimethoxystyrylsulfonyl)methyl]phenylamino}acetate (ON 01910.Na), which is in phase III trials for myelodysplastic syndromes (MDS) associated with aberrant expression of cyclin D proteins.

Publication types

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

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Biological Availability
  • Cell Line, Tumor
  • Drug Resistance, Multiple
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Female
  • Glycine / analogs & derivatives*
  • Glycine / chemical synthesis
  • Glycine / chemistry
  • Glycine / pharmacology
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasm Transplantation
  • Protein Kinase Inhibitors / chemical synthesis*
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry
  • Sulfones / pharmacology
  • Transplantation, Heterologous


  • Antineoplastic Agents
  • Protein Kinase Inhibitors
  • Sulfones
  • ON 01910
  • Glycine