title: Identification of pyrimidine derivatives as hSMG-1 inhibitors.
abstract: hSMG-1 kinase plays a dual role in a highly conserved RNA surveillance pathway termed nonsense-mediated RNA decay (NMD) and in cellular genotoxic stress response. Since deregulation of cellular responses to stress contributes to tumor growth and resistance to chemotherapy, hSMG-1 is a potential target for cancer treatment. From our screening efforts, we have identified pyrimidine derivatives as hSMG-1 kinase inhibitors. We report structure-based optimization of this pan-kinase scaffold to improve its biochemical profile and overall kinome selectivity, including mTOR and CDK, to generate the first reported selective hSMG-1 tool compound.
authors.affiliation: Worldwide Medicinal Chemistry, Pfizer, 200 Cambridgepark Drive, Cambridge, MA 02140, USA. ariamala.gopalsamy@pfizer.com
authors.forename: Ariamala
authors.initials: A
authors.lastname: Gopalsamy
authors.forename: Eric M
authors.initials: EM
authors.lastname: Bennett
authors.forename: Mengxiao
authors.initials: M
authors.lastname: Shi
authors.forename: Wei-Guo
authors.initials: WG
authors.lastname: Zhang
authors.forename: Joel
authors.initials: J
authors.lastname: Bard
authors.forename: Ker
authors.initials: K
authors.lastname: Yu
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D004791:Enzyme Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011743:Pyrimidines; D017346:Protein Serine-Threonine Kinases; C514704:SMG1 protein, human