Imidazole piperazines: SAR and development of a potent class of cyclin-dependent kinase inhibitors with a novel binding mode.
A piperazine series of cyclin-dependent kinase (CDK) inhibitors have been identified. The compounds exhibit excellent physiochemical properties and a novel binding mode, whereby a bridging interaction via a water molecule with Asp 86 of CDK2, leads to selectivity for the CDK family of enzymes over other kinases. Piperazines 2e and 2i were subsequently shown to inhibit tumour growth when dosed orally in a nude mouse xenograft study. Additional chemical series that exploit this unexpected interaction with Asp 86 are also described.
Finlay
M Raymond V
MR
Cancer and Infection Research Area, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. ray.finlay@astrazeneca.com
Acton
David G
DG
Andrews
David M
DM
Barker
Andrew J
AJ
Dennis
Michael
M
Fisher
Eric
E
Graham
Mark A
MA
Green
Clive P
CP
Heaton
David W
DW
Karoutchi
Galith
G
Loddick
Sarah A
SA
Morgentin
Rémy
R
Roberts
Andrew
A
Tucker
Julie A
JA
Weir
Hazel M
HM
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques; D051357:Cyclin-Dependent Kinase 2 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D010879:Piperazines; D001224:Aspartic Acid; D051357:Cyclin-Dependent Kinase 2; D018844:Cyclin-Dependent Kinases