title: Design, synthesis, and biological activity of novel Magmas inhibitors.
abstract: Magmas (mitochondria associated, granulocyte-macrophage colony stimulating factor signaling molecule), is a highly conserved and essential gene, expressed in all cell types. We designed and synthesized several small molecule Magmas inhibitors (SMMI) and assayed their effects on proliferation in yeast. We found that the most active compound 9 inhibited growth at the 4 μM scale. This compound was shown by fluorometric titration to bind to Magmas with a K(d)=33 μM. Target specificity of the lead compound was established by demonstrating direct binding of the compound to Magmas and by genetic studies. Molecular modeling suggested that the inhibitor bound at the predicted site in Magmas.
authors.affiliation: Pediatric Hematology/Oncology, Yale University Medical School, New Haven, CT 06510, United States. paul.jubinsky@yale.edu
authors.forename: Paul T
authors.initials: PT
authors.lastname: Jubinsky
authors.forename: Mary K
authors.initials: MK
authors.lastname: Short
authors.forename: Mohmoud
authors.initials: M
authors.lastname: Ghanem
authors.forename: Bhaskar C
authors.initials: BC
authors.lastname: Das
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015003:Yeasts / Q000187:drug effects
chemical_list: D024101:Mitochondrial Proteins; D054852:Small Molecule Libraries; D016178:Granulocyte-Macrophage Colony-Stimulating Factor