Targeting protein kinases for bone disease: discovery and development of Src inhibitors.
The dynamic and highly regulated processes of bone remodeling involve two major cells, osteoclasts and osteoblasts, both of which command a multitude of cellular signaling pathways involving protein kinases. Of the possible kinases in these cells, Src tyrosine kinase stands out as a promising therapeutic target for bone disease as validated by Src knockout mouse studies and in vitro cellular experiments, suggesting a regulatory role for Src in both osteoclasts (positive) and osteoblasts (negative). Advances in structural studies involving both Src and non-Src family kinases, in activated and unactivated protein states, have uncovered key binding site interactions that have led to the design of potent Src inhibitors. The lead compounds originate from a variety of synthetic templates and have demonstrated nM potency in enzymatic/binding assays and efficacy in animal models of bone disease. This review will provide a current understanding of critical Src signalling pathways in osteoclasts and osteoblasts, while detailing the structure-based design and screening-based lead discovery of Src inhibitors to be developed as therapeutic agents for bone disease.
Metcalf
Chester A
CA
ARIAD Pharmaceuticals, Inc., 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. chet.metcalf@ariad.com
van Schravendijk
Marie Rose
MR
Dalgarno
David C
DC
Sawyer
Tomi K
TK
D000818:Animals; D001685:Biological Factors / Q000737:chemistry / Q000494:pharmacology; D001847:Bone Diseases / Q000188:drug therapy / Q000201:enzymology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D001842:Bone and Bones / Q000166:cytology / Q000201:enzymology; D020650:Combinatorial Chemistry Techniques; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D018716:Molecular Mimicry; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology; D010024:Osteoporosis / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D018909:src Homology Domains; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
D001685:Biological Factors; D004791:Enzyme Inhibitors; D010455:Peptides; D019061:src-Family Kinases