title: Design and synthesis of 2-amino-pyrazolopyridines as Polo-like kinase 1 inhibitors.
abstract: A series of 2-amino-pyrazolopyridines was designed and synthesized as Polo-like kinase (Plk) inhibitors based on a low micromolar hit. The SAR was developed to provide compounds exhibiting low nanomolar inhibitory activity of Plk1; the phenotype of treated cells is consistent with Plk1 inhibition. A co-crystal structure of one of these compounds with zPlk1 confirms an ATP-competitive binding mode.
authors.affiliation: Department of Biology, Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard Suite 400, South San Francisco, CA 94080, USA. rfucini@sunesis.com
authors.forename: Raymond V
authors.initials: RV
authors.lastname: Fucini
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Hanan
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Romanowski
authors.forename: Robert A
authors.initials: RA
authors.lastname: Elling
authors.forename: Willard
authors.initials: W
authors.lastname: Lew
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Barr
authors.forename: Jiang
authors.initials: J
authors.lastname: Zhu
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Yoburn
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Fahr
authors.forename: Junfa
authors.initials: J
authors.lastname: Fan
authors.forename: Yafan
authors.initials: Y
authors.lastname: Lu
authors.forename: Phuongly
authors.initials: P
authors.lastname: Pham
authors.forename: Ingrid C
authors.initials: IC
authors.lastname: Choong
authors.forename: Erica C
authors.initials: EC
authors.lastname: VanderPorten
authors.forename: Minna
authors.initials: M
authors.lastname: Bui
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Marc J
authors.initials: MJ
authors.lastname: Evanchik
authors.forename: Wenjin
authors.initials: W
authors.lastname: Yang
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D020816:Amino Acid Motifs; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008968:Molecular Conformation; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors*; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000097869:Polo-Like Kinase 1
chemical_list: D000255:Adenosine Triphosphate; D018797:Cell Cycle Proteins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D011720:Pyrazoles; D011725:Pyridines; D000097869:Polo-Like Kinase 1; C118531:pyrazolopyridine