title: Discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as novel PKM2 activators.
abstract: The M2 isoform of pyruvate kinase is an emerging target for antitumor therapy. In this letter, we describe the discovery of 2-((1H-benzo[d]imidazol-1-yl)methyl)-4H-pyrido[1,2-a]pyrimidin-4-ones as potent and selective PKM2 activators which were found to have a novel binding mode. The original lead identified from high throughput screening was optimized into an efficient series via computer-aided structure-based drug design. Both a representative compound from this series and an activator described in the literature were used as molecular tools to probe the biological effects of PKM2 activation on cancer cells. Our results suggested that PKM2 activation alone is not sufficient to alter cancer cell metabolism.
authors.affiliation: Oncology Medicinal Chemistry, Pfizer Worldwide Research & Development, San Diego, CA 92121, USA.
authors.forename: Chuangxing
authors.initials: C
authors.lastname: Guo
authors.forename: Angelica
authors.initials: A
authors.lastname: Linton
authors.forename: Mehran
authors.initials: M
authors.lastname: Jalaie
authors.forename: Susan
authors.initials: S
authors.lastname: Kephart
authors.forename: Martha
authors.initials: M
authors.lastname: Ornelas
authors.forename: Mason
authors.initials: M
authors.lastname: Pairish
authors.forename: Samantha
authors.initials: S
authors.lastname: Greasley
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.forename: Karen
authors.initials: K
authors.lastname: Maegley
authors.forename: Michael
authors.initials: M
authors.lastname: Hickey
authors.forename: John
authors.initials: J
authors.lastname: Li
authors.forename: Xin
authors.initials: X
authors.lastname: Wu
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ji
authors.forename: Zhi
authors.initials: Z
authors.lastname: Xie
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry*; D001665:Binding Sites; D002352:Carrier Proteins / Q000819:agonists* / Q000378:metabolism; D002460:Cell Line; D017076:Computer-Aided Design; D004353:Drug Evaluation, Preclinical; D057166:High-Throughput Screening Assays; D006801:Humans; D007700:Kinetics; D008565:Membrane Proteins / Q000819:agonists* / Q000378:metabolism; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013963:Thyroid Hormones / Q000819:agonists* / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D001562:Benzimidazoles; D002352:Carrier Proteins; D008565:Membrane Proteins; D011744:Pyrimidinones; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C031000:benzimidazole