Publications by authors named "Manfred Weigele"
Background: Mutations in LRRK2 are associated with familial and sporadic Parkinson's disease (PD). Subjects with PD caused by LRRK2 mutations show pleiotropic pathology that can involve inclusions containing α-synuclein, tau or neither protein. The mechanisms by which mutations in LRRK2 lead to this pleiotropic pathology remain unknown.
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- 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.
Novel bone-targeted Src tyrosine kinase inhibitor drug discovery.
Curr Opin Drug Discov Devel
September 2003
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.
View Article and Find Full Text PDFThe 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.
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- Novel inhibitors targeting Src tyrosine kinase based on a purine template have been developed.
- Drug design focused on enhancing bone-targeting capabilities by modifying specific positions (2 and 6) of known purine compounds.
- Compound 3d emerged as a strong Src inhibitor, demonstrating selectivity over various other protein kinases.
Src 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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