Publications by authors named "Mary Ram"
SAR of carbon-linked, 2-substituted purines: synthesis and characterization of AP23451 as a novel bone-targeted inhibitor of Src tyrosine kinase with in vivo anti-resorptive activity.
Chem Biol Drug Des
February 2008
Article Synopsis
- The Src gene is implicated in osteoclast-mediated bone resorption, making it a potential target for osteoporosis treatment.
- A new compound, AP23451, was identified as a potent Src inhibitor that has bone-targeting properties, enhancing its effectiveness in reducing bone loss.
- AP23451 showed strong inhibition of Src in vitro (IC50 = 68 nm) and significantly decreased hypercalcemia in vivo, while a similar compound without bone-targeting action (AP23517) was much less effective.
Article Synopsis
- Src is a key tyrosine kinase involved in various cellular processes such as growth, differentiation, and migration, and its abnormal signaling is associated with diseases like cancer and osteoporosis.
- Research has focused on developing small-molecule inhibitors of Src, including AP23451 and AP23464, which effectively bind to Src’s ATP pocket to inhibit its activity and prevent cancer metastasis and bone resorption.
- Crystal structures of Src-inhibitor complexes reveal specific interactions between the inhibitors and Src, particularly highlighting how the design of these inhibitors, especially the 3-hydroxyphenethyl N9 substituent, enhances binding affinity and induces structural changes in Src that facilitate inhibition.
The design of bone-targeted pyrido[2,3-d]pyrimidin-7-ones as Src tyrosine kinase inhibitors is described. Leveraging SAR from known compounds and using structure-based methods, we were able to rapidly incorporate bone binding components, which maintained, and even increased potency against the target enzyme. Compound 4 displayed a high affinity for hydroxyapatite, a major constituent of bone, and demonstrated antiresoprtive activity in our cell-based assay.
View Article and Find Full Text PDFNovel bone-targeted 2,6,9-trisubstituted purine template-based inhibitors of Src tyrosine kinase are described. Drug design studies of known purine compounds revealed that both positions-2 and -6 were suitable for incorporating bone-seeking moieties. A variety of bone-targeting groups with different affinity to hydroxyapatite were utilized in the study.
View Article and Find Full Text PDFSrc tyrosine kinase is a therapeutic target for bone diseases that has been validated by gene knockout studies. Furthermore, in vitro cellular studies implicate that Src has a positive regulatory role in osteoclasts and a negative regulatory role in osteoblasts. The potential use of Src inhibitors for osteoporosis therapy has been previously shown by novel bone-targeted ligands of the Src SH2 (e.
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