Preparation of kinase-biased compounds in the search for lead inhibitors of kinase targets.
This work describes the preparation of approximately 13,000 compounds for rapid identification of hits in high-throughput screening (HTS). These compounds were designed as potential serine/threonine or tyrosine kinase inhibitors. The library consists of various scaffolds, e.g., purines, oxindoles, and imidazoles, whereby each core scaffold generally includes the hydrogen bond acceptor/donor properties known to be important for kinase binding. Several of these are based upon literature kinase templates, or adaptations of them to provide novelty. The routes to their preparation are outlined. A variety of automation techniques were used to prepare >500 compounds per scaffold. Where applicable, scavenger resins were employed to remove excess reagents and when necessary, preparative high performance liquid chromatography (HPLC) was used for purification. These compounds were screened against an 'in-house' kinase panel. The success rate in HTS was significantly higher than the corporate compound collection.
Lai
Justine Y Q
JY
Millennium Pharmaceuticals R&D Limited, Granta Park, Great Abington, Cambridge CB1 6ET, United Kingdom.
Langston
Steven
S
Adams
Ruth
R
Beevers
Rebekah E
RE
Boyce
Richard
R
Burckhardt
Svenja
S
Cobb
James
J
Ferguson
Yvonne
Y
Figueroa
Eva
E
Grimster
Neil
N
Henry
Andrew H
AH
Khan
Nawaz
N
Jenkins
Kerry
K
Jones
Mark W
MW
Judkins
Robert
R
Major
Jeremy
J
Masood
Abid
A
Nally
James
J
Payne
Helen
H
Payne
Lloyd
L
Raphy
Gilles
G
Raynham
Tony
T
Reader
John
J
Reader
Valérie
V
Reid
Alison
A
Ruprah
Parminder
P
Shaw
Michael
M
Sore
Hannah
H
Stirling
Matthew
M
Talbot
Adam
A
Taylor
Jess
J
Thompson
Stephen
S
Wada
Hiroki
H
Walker
David
D
D015195:Drug Design; D007093:Imidazoles / Q000138:chemical synthesis / Q000494:pharmacology; D007211:Indoles / Q000138:chemical synthesis / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology; D009281:Naphthalenes / Q000138:chemical synthesis / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology
D007093:Imidazoles; D007211:Indoles; D007546:Isoquinolines; D009281:Naphthalenes; D047428:Protein Kinase Inhibitors; D011687:Purines; D011743:Pyrimidines