title: 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.
abstract: 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.
authors.affiliation: Department of Oncological Sciences, Icahn Medical Institute, Mount Sinai School of Medicine, New York, New York 10029-6514, USA. r.reddy@mssm.edu
authors.forename: M V Ramana
authors.initials: MV
authors.lastname: Reddy
authors.forename: Padmavathi
authors.initials: P
authors.lastname: Venkatapuram
authors.forename: Muralidhar R
authors.initials: MR
authors.lastname: Mallireddigari
authors.forename: Venkat R
authors.initials: VR
authors.lastname: Pallela
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cosenza
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Robell
authors.forename: Balaiah
authors.initials: B
authors.lastname: Akula
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Hoffman
authors.forename: E Premkumar
authors.initials: EP
authors.lastname: Reddy
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001682:Biological Availability; D045744:Cell Line, Tumor; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005998:Glycine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D013450:Sulfones; C507134:ON 01910; D005998:Glycine