title: Identification of novel small molecules that inhibit protein-protein interactions between MAGE and KAP-1.
abstract: The Class I MAGE proteins are normally expressed only in developing germ cells but are often aberrantly expressed in malignancies, particularly melanoma, making them good therapeutic targets. MAGE proteins promote tumor survival by binding to the RBCC region of KAP-1 and suppressing p53. Although, suppression of MAGE expression, by RNA interference, relieves p53 suppression and inhibits tumor growth, its therapeutic uses are limited by lack of methods for systemic delivery of small interfering RNA. To overcome this barrier, we sought to discover chemical compounds that inhibit binding between MAGE and KAP-1 proteins. Based on previously published effects of MAGE suppression, we developed a strategy for screening a small molecule library based on selective death of MAGE positive cells, activation of p53 and lack of caspase activity. We screened the Maybridge HitFinder library of compounds and eight compounds fulfilled these criteria. Seven of these compounds interfered with co-precipitation of MAGE and KAP-1, and three interfered with binding of MAGE and KAP-1 in a mammalian two hybrid assay. We now report identification of three potential compounds that interfere with MAGE/KAP-1 binding and can be developed as novel chemo-therapeutic agents for treatment of advanced melanoma and other cancers.
authors.affiliation: Department of Dermatology, The University of Wisconsin School of Medicine and Public Health, Madison, WI 53706, USA. nbhatia@dermatology.wisc.edu
authors.forename: Neehar
authors.initials: N
authors.lastname: Bhatia
authors.forename: Bing
authors.initials: B
authors.lastname: Yang
authors.forename: Tony Z
authors.initials: TZ
authors.lastname: Xiao
authors.forename: Noel
authors.initials: N
authors.lastname: Peters
authors.forename: Michael F
authors.initials: MF
authors.lastname: Hoffmann
authors.forename: B Jack
authors.initials: BJ
authors.lastname: Longley
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D000076183:Tripartite Motif-Containing Protein 28
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D012097:Repressor Proteins; C101116:TRIM28 protein, human; D000076183:Tripartite Motif-Containing Protein 28