Bisphosphonate Conjugates with RON Kinase Inhibitors

Description:

Researchers at TGen and the University of Utah are developing bisphosphonate (diphosphonic acid) conjugates with RON kinase inhibitor compounds for treating metastatic cancers, such as breast cancer, and diseases, such as osteoporosis and osteoarthritis, associated with bone destruction.  These conjugated bisphosphonates combine the anti-mitotic, anti-angiogenic, and bone-targeting properties of bisphosphonates with kinase inhibitor activity for improved pharmaceutical performance.

 

Cancer, and in particular, metastatic cancer remains one of the most challenging diseases to treat. Metastatic cancers can disseminate to distant organs, even before diagnosis of the primary tumor, where it can remain in a clinically undetectable state for many years.  Bone metastases are a common site of recurrence for many types of cancer (e.g., breast cancer), may influence cancer progression in other sites, and are often osteolytic due to activation of bone-resorbing resident macrophages known as osteoclasts.  Bisphosphonates are known to affect bone physiology, inhibit bone resorption (including apoptosis of osteoclasts), and prevent age-related bone loss in advanced cancers that have spread to the bone.  Current treatment strategies for bone metastasis include inhibiting osteoclast function with bisphosphonates and targeting the RANKL/RANK signaling pathway in osteoclasts using denosumab, but this strategy has been ineffective for many patients. 

 

For breast cancer patients, research has shown that macrophage-stimulating protein (MSP) and its receptor, RON (receptor originated from nantes) tyrosine kinase, are associated with an increased metastasis to bone, and other sites, and a decreased overall survival.  Similar to the findings in cancer, RON tyrosine kinase has also been shown to play a role in bone loss due to non-cancer diseases, such as osteoporosis.  While these findings for the RON tyrosine kinase may provide a new treatment pathway for cancer and other bone destructive diseases, current multi-kinase inhibitors in clinical Phase 1 and 2 trials for multiple cancers have shown poor pharmacokinetic properties and low bone tissue permeability when the compounds are administered orally. 

 

Through the inventive direct conjugation of bisphosphonate functional moieties on to RON kinase inhibitors, the pharmaceutic performance of these drugs and treatment of bone metastases and other bone destructive diseases can be improved.  Further benefits of these new conjugates, which specifically target the osteoclast and resident tissue macrophage cells dependent on the RON function to support metastasis, is that the conjugates may be delivered by standard methods, such as orally or intravenous infusion, and may replace other more toxic therapies.  The bisphosphonate conjugates of the RON kinase inhibitor drugs may additionally improve the response rate in patients with bone metastases, the median progression free survival, and the median overall survival through the dual effects of blocking osteolysis and enhancing anti-tumor immunity.

 

Patent Information:
For Information, Contact:
Katie Bray
Intellectual Property Counsel
The Translational Genomics Research Institute
kbray@tgen.org
Inventors:
Hariprasad Vankayalapati
Sunil Sharma
Alana Welm
Keywords: