Kinase Inhibitor Compounds Targeting Fms and Kit Specificity
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Solution Overview
Problem
Current treatments for protein kinase-mediated diseases lack effective inhibitors that can specifically target kinases such as Fms and Kit, which are involved in various conditions including cancer, without significant off-target effects.
Innovation Solution
Development of novel compounds, specifically those of Formula I, II, and III, which act as kinase inhibitors with high specificity for Fms, Kit, and other protein kinases, including their mutated forms, offering therapeutic benefits for conditions like cancer and inflammatory diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for protein kinase-mediated diseases are used, then therapeutic effects are achieved, but significant off-target effects occur and specificity for target kinases (Fms, Kit) is insufficient
Solution Approach 1:
The patent applies local quality by designing compounds with specific structural features (substituents at defined positions in the core structure) that confer selectivity for target kinases. Different substituent patterns (R1-R6 groups) are engineered to interact with specific residues in the kinase binding pocket, ensuring the compound binds preferentially to Fms, Kit and related kinases while avoiding off-target proteins.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the compound structure (different core structures, substituent types, linker lengths) to optimize binding affinity and selectivity. The IC50 values are tuned through these parameter variations to achieve potent inhibition (below 100 nM) of target kinases while maintaining specificity.
2Reliability
If novel compounds of Formula I, II, and III are developed to inhibit target kinases, then potent inhibition with IC50 values below 100 nM is achieved, but the complexity of identifying optimal compounds increases
Solution Approach 1:
The patent applies segmentation by dividing the compound into distinct functional modules: a core structure (various aromatic or hetero aromatic rings), substituent groups (R1-R6 with specific chemical properties), and linker regions. This modular approach allows systematic optimization of each segment to achieve potent inhibition while simplifying the identification process through structure-activity relationship analysis.
Solution Approach 2:
The patent employs universality by designing a core structure with multiple substitutable positions that can accommodate various functional groups. This universal scaffold can be adapted to target different kinases (Fms, Kit, and related kinases) by changing substituents, allowing a single compound design strategy to achieve potent inhibition across multiple target kinases.
Data Source
AI summary
Compounds Formula I:and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on at least one of Fms protein kinase or Kit protein kinase. Also described are methods of use thereof to treat diseases and conditions, including diseases and conditions associated with activity of Fms protein kinases and/or Kit protein kinases, including rheumatoid arthiritis, osteoarthritis, osteoporosis, peri-prosthetic osteolysis, systemic sclerosis, demyelinating disorders, multiple sclerosis, Charcot Marie Tooth syndrome, amyotrophic lateral sclerosis, Alzheimer's disease, Parkinson's disease, ulcerative colitis, Crohn's disease, immune thrombocytopenic purpura, myelopreparation for autologous transplantation, transplant rejection, nephritis, nephropathy, type I diabetes, acute pain, inflammatory pain, neuropathic pain, breast cancer, prostate cancer, pancreatic cancer, lung cancer, ovarian cancer, gliomas, glioblastomas, neurofibromatosis, osteolytic bone metastases, and giant cell tumors.