HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

Novel bone-targeted Src tyrosine kinase inhibitor drug discovery.

Abstract
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.
AuthorsWilliam C Shakespeare, Chester A Metcalf 3rd, Yihan Wang, Raji Sundaramoorthi, Terence Keenan, Manfred Weigele, Regine S Bohacek, David C Dalgarno, Tomi K Sawyer
JournalCurrent opinion in drug discovery & development (Curr Opin Drug Discov Devel) Vol. 6 Issue 5 Pg. 729-41 (Sep 2003) ISSN: 1367-6733 [Print] England
PMID14579523 (Publication Type: Journal Article, Review)
Chemical References
  • AP22408
  • AP23236
  • Diphosphonates
  • Phenols
  • Purines
  • src-Family Kinases
Topics
  • Animals
  • Bone Neoplasms (drug therapy, enzymology)
  • Bone Resorption (drug therapy, enzymology)
  • Bone and Bones (drug effects, enzymology)
  • Diphosphonates (pharmacology, therapeutic use)
  • Drug Design
  • Humans
  • Models, Molecular
  • Osteoclasts (drug effects, enzymology)
  • Osteoporosis (drug therapy, enzymology)
  • Phenols (pharmacology, therapeutic use)
  • Protein Conformation
  • Purines (pharmacology, therapeutic use)
  • Structure-Activity Relationship
  • src Homology Domains
  • src-Family Kinases (antagonists & inhibitors, chemistry)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: