Novel bone-targeted Src tyrosine kinase inhibitor drug discovery.
Bone-targeted Src tyrosine kinase (STK) inhibitors have recently been developed for the treatment of osteoporosis and cancer-related bone diseases. The concept of bone targeting derives from bisphosphonates, and from the evolution of such molecules in terms of therapeutic efficacy for the treatment of bone disorders. Interestingly, some of the earliest bisphosphonates were recognized for their ability to inhibit calcium carbonate precipitation (scaling) by virtue of their affinity to chelate calcium. This chelating property was subsequently exploited in the development of bisphosphonate analogs as inhibitors of the bone-resorbing cells known as osteoclasts, giving rise to breakthrough medicines, such as Fosamax (for the treatment of osteoporosis) and Zometa (for the treatment of osteoporosis and bone metastases). Relative to these milestone achievements, there is a tremendous opportunity to explore beyond the limited chemical space (functional group diversity) of such bisphosphonates to design novel bone-targeting moieties, which may be used to develop other classes of promising small-molecule drugs affecting different biological pathways. Here, we review studies focused on bone-targeted inhibitors of STK, a key enzyme in osteoclast-dependent bone resorption. Two strategies are described relative to bone-targeted STK inhibitor drug discovery: (i) the development of novel Src homology (SH)-2 inhibitors incorporating non-hydrolyzable phosphotyrosine mimics and exhibiting molecular recognition and bone-targeting properties, leading to the in vivo-effective lead compound AP-22408; and (ii) the development of novel ATP-based Src kinase inhibitors incorporating bone-targeting moieties, leading to the in vivo-effective lead compound AP-23236. In summary, AP-22408 and AP-23236, which differ mechanistically by virtue of blocking Src-dependent non-catalytic or catalytic activities in osteoclasts, exemplify ARIAD Pharmaceuticals' structure-based design of novel bone-targeted lead compounds, successfully achieving in vivo proof-of-concept and providing the framework for the next-generation molecules that have further advanced, in terms of preclinical studies, for the treatment of osteoporosis and related bone diseases, including osteolytic bone metastases.
Shakespeare
William C
WC
ARIAD Pharmaceuticals Inc, 26 Landsdowne Street, Cambridge, MA 02139-4234, USA. william.shakespeare@ariad.com
Metcalf
Chester A
CA
Wang
Yihan
Y
Sundaramoorthi
Raji
R
Keenan
Terence
T
Weigele
Manfred
M
Bohacek
Regine S
RS
Dalgarno
David C
DC
Sawyer
Tomi K
TK
D000818:Animals; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology; D001862:Bone Resorption / Q000188:drug therapy / Q000201:enzymology; D001842:Bone and Bones / Q000187:drug effects* / Q000201:enzymology*; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology; D010024:Osteoporosis / Q000188:drug therapy / Q000201:enzymology; D010636:Phenols / Q000494:pharmacology* / Q000627:therapeutic use; D011487:Protein Conformation; D011687:Purines / Q000494:pharmacology* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D018909:src Homology Domains; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry
C413184:AP22408; C479343:AP23236; D004164:Diphosphonates; D010636:Phenols; D011687:Purines; D019061:src-Family Kinases