title: The discovery of a new structural class of cyclin-dependent kinase inhibitors, aminoimidazo[1,2-a]pyridines.
abstract: The protein kinase family represents an enormous opportunity for drug development. However, the current limitation in structural diversity of kinase inhibitors has complicated efforts to identify effective treatments of diseases that involve protein kinase signaling pathways. We have identified a new structural class of protein serine/threonine kinase inhibitors comprising an aminoimidazo[1,2-a]pyridine nucleus. In this report, we describe the first successful use of this class of aza-heterocycles to generate potent inhibitors of cyclin-dependent kinases that compete with ATP for binding to a catalytic subunit of the protein. Co-crystal structures of CDK2 in complex with lead compounds reveal a unique mode of binding. Using this knowledge, a structure-based design approach directed this chemical scaffold toward generating potent and selective CDK2 inhibitors, which selectively inhibited the CDK2-dependent phosphorylation of Rb and induced caspase-3-dependent apoptosis in HCT 116 tumor cells. The discovery of this new class of ATP-site-directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis for a new medicinal chemistry tool to be used in the search for effective treatments of cancer and other diseases that involve protein kinase signaling pathways.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. hamdouchi_chafiq@lilly.com
authors.forename: Chafiq
authors.initials: C
authors.lastname: Hamdouchi
authors.forename: Heather
authors.initials: H
authors.lastname: Keyser
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Collins
authors.forename: Carlos
authors.initials: C
authors.lastname: Jaramillo
authors.forename: Jose Eugenio
authors.initials: JE
authors.lastname: De Diego
authors.forename: Charles D
authors.initials: CD
authors.lastname: Spencer
authors.forename: Jack Alan
authors.initials: JA
authors.lastname: Dempsey
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Anderson
authors.forename: Tillie
authors.initials: T
authors.lastname: Leggett
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Stamm
authors.forename: Richard M
authors.initials: RM
authors.lastname: Schultz
authors.forename: Scott A
authors.initials: SA
authors.lastname: Watkins
authors.forename: Kim
authors.initials: K
authors.lastname: Cocke
authors.forename: Stephanie
authors.initials: S
authors.lastname: Lemke
authors.forename: Teresa F
authors.initials: TF
authors.lastname: Burke
authors.forename: Richard P
authors.initials: RP
authors.lastname: Beckmann
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Dixon
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Gurganus
authors.forename: Nancy B
authors.initials: NB
authors.lastname: Rankl
authors.forename: Keith A
authors.initials: KA
authors.lastname: Houck
authors.forename: Faming
authors.initials: F
authors.lastname: Zhang
authors.forename: Michal
authors.initials: M
authors.lastname: Vieth
authors.forename: Juan
authors.initials: J
authors.lastname: Espinosa
authors.forename: David E
authors.initials: DE
authors.lastname: Timm
authors.forename: Robert M
authors.initials: RM
authors.lastname: Campbell
authors.forename: Bharvin K R
authors.initials: BK
authors.lastname: Patel
authors.forename: Harold B
authors.initials: HB
authors.lastname: Brooks
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D042846:CDC2-CDC28 Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D051357:Cyclin-Dependent Kinase 2; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D016160:Retinoblastoma Protein; D000255:Adenosine Triphosphate; D042846:CDC2-CDC28 Kinases; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases