Pyrimidine Analogs Modulate Cell Cycle Checkpoints to Reduce Side Effects
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Solution Overview
Problem
Current cancer treatments often have a low therapeutic index, causing significant side effects due to their broad-spectrum activity that affects both cancerous and normal cells, leading to severe side effects and limited efficacy in targeting cancer cells specifically.
Innovation Solution
Development of novel compounds that act as targeted mechanism-based modulators of cell cycle checkpoints, particularly checkpoint kinase 1 (Chk1), and their pharmaceutical compositions for use in treating cancer and other diseases, in combination with checkpoint kinase inhibitors to enhance therapeutic index and reduce side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If broad-spectrum cancer treatments are used to treat cancer cells, then cancer cells are killed, but normal cells are also affected causing severe side effects
Solution Approach 1:
The treatment approach is segmented into two distinct components: checkpoint kinase inhibitors (affecting both cancer and normal cells) and ATR inhibitors (selectively affecting cancer cells with replication stress). This segmentation allows the combination to achieve broader anti-cancer activity while sparing normal cells, thereby improving the therapeutic index and reducing side effects.
Solution Approach 2:
The patent applies local quality by making the treatment selectively effective in cancer cells with specific characteristics (replication stress, defective ATR signaling) while being less effective in normal cells. The ATR inhibitor component provides localized therapeutic action specifically where replication stress exists, improving target specificity and reducing harm to normal tissues.
2Reliability
If conventional chemotherapy agents are used to suppress DNA synthesis, then cancer cell proliferation is inhibited, but the treatment lacks specificity and affects normal dividing cells
Solution Approach 1:
The treatment is divided into two agents with complementary specificities: checkpoint kinase inhibitors provide broad-spectrum anti-proliferative activity, while ATR inhibitors provide selective targeting of cancer cells with replication stress. This segmentation enables the combination to achieve both broad anti-cancer efficacy and specific targeting of malignant cells.
Solution Approach 2:
The patent creates a composite therapeutic approach by combining two different molecular mechanisms (checkpoint kinase inhibition and ATR inhibition) into a single treatment regimen. This composite strategy achieves synergistic effects where the combination provides both broad anti-cancer activity and specific targeting, overcoming the limitations of either agent alone.
Data Source
AI summary
In its many embodiments, the present invention provides a novel class of pyrimidine analogs as targeted mechanism-based modulators of cell cycle checkpoints. Cancers and/or malignancies can be treated by administration of a cell cycle checkpoint modulator of the invention. Also discussed are suitable combinations of the cell cycle checkpoint modulator with a checkpoint kinase inhibitor to produce synergistic apoptosis in cancer cells. The invention also includes methods of treating cancers by administering the combination of the cell cycle checkpoint modulator and the checkpoint kinase inhibitor, pharmaceutical compositions comprising the cell cycle checkpoint modulator as well as combinations and pharmaceutical kits. An example cell cycle checkpoint modulator is shown below: formula (I).