title: The discovery of novel benzofuran-2-carboxylic acids as potent Pim-1 inhibitors.
abstract: Novel benzofuran-2-carboxylic acids, exemplified by 29, 38 and 39, have been discovered as potent Pim-1 inhibitors using fragment based screening followed by X-ray structure guided medicinal chemistry optimization. The compounds demonstrate potent inhibition against Pim-1 and Pim-2 in enzyme assays. Compound 29 has been tested in the Ambit 442 kinase panel and demonstrates good selectivity for the Pim kinase family. X-ray structures of the inhibitor/Pim-1 binding complex reveal important salt-bridge and hydrogen bond interactions mediated by the compound's carboxylic acid and amino groups.
authors.affiliation: Department of Medicinal Chemistry, Drug and Biomaterial R&D, Genzyme Corp., 153 Second Avenue, Waltham, MA 02451, USA. yibin.xiang@genzyme.com
authors.forename: Yibin
authors.initials: Y
authors.lastname: Xiang
authors.forename: Bradford
authors.initials: B
authors.lastname: Hirth
authors.forename: Gary
authors.initials: G
authors.lastname: Asmussen
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Biemann
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Bishop
authors.forename: Andrew
authors.initials: A
authors.lastname: Good
authors.forename: Maria
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Tatiana
authors.initials: T
authors.lastname: Gladysheva
authors.forename: Annuradha
authors.initials: A
authors.lastname: Jain
authors.forename: Katherine
authors.initials: K
authors.lastname: Jancsics
authors.forename: Jinyu
authors.initials: J
authors.lastname: Liu
authors.forename: Markus
authors.initials: M
authors.lastname: Metz
authors.forename: Andrew
authors.initials: A
authors.lastname: Papoulis
authors.forename: Renato
authors.initials: R
authors.lastname: Skerlj
authors.forename: J David
authors.initials: JD
authors.lastname: Stepp
authors.forename: Ronnie R
authors.initials: RR
authors.lastname: Wei
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000737:chemistry*; D002264:Carboxylic Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; 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; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors*; D051381:Rats
chemical_list: D001572:Benzofurans; D002264:Carboxylic Acids; D004791:Enzyme Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1