Identification of novel p38alpha MAP kinase inhibitors using fragment-based lead generation.
We describe the structure-guided optimization of the molecular fragments 2-amino-3-benzyloxypyridine 1 (IC(50) 1.3 mM) and 3-(2-(4-pyridyl)ethyl)indole 2 (IC(50) 35 microM) identified using X-ray crystallographic screening of p38alpha MAP kinase. Using two separate case studies, the article focuses on the key compounds synthesized, the structure-activity relationships and the binding mode observations made during this optimization process, resulting in two potent lead series that demonstrate significant increases in activity. We describe the process of compound elaboration either through the growing out from fragments into adjacent pockets or through the conjoining of overlapping fragments and demonstrate that we have exploited the mobile conserved activation loop, consisting in part of Asp168-Phe169-Gly170 (DFG), to generate significant improvements in potency and kinase selectivity.
Gill
Adrian L
AL
Astex Technology, 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. a.gill@astex-technology.com
Frederickson
Martyn
M
Cleasby
Anne
A
Woodhead
Steven J
SJ
Carr
Maria G
MG
Woodhead
Andrew J
AJ
Walker
Margaret T
MT
Congreve
Miles S
MS
Devine
Lindsay A
LA
Tisi
Dominic
D
O'Reilly
Marc
M
Seavers
Lisa C A
LC
Davis
Deborah J
DJ
Curry
Jayne
J
Anthony
Rachel
R
Padova
Alessandro
A
Murray
Christopher W
CW
Carr
Robin A E
RA
Jhoti
Harren
H
D000631:Aminopyridines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D000631:Aminopyridines; D004791:Enzyme Inhibitors; D007211:Indoles; D008024:Ligands; D048051:p38 Mitogen-Activated Protein Kinases