Quinoline RAD52 Inhibitors for BRCA1/2-Deficient Cancer
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Solution Overview
Problem
There is a need for improved RAD52 modulation compounds to treat cancers and disorders associated with RAD52, as existing methods are inadequate in targeting cancer cells with mutations in the BRCA1/2 and PALB2 genes.
Innovation Solution
Development of quinoline derivatives and their pharmaceutically acceptable salts that modulate RAD52 activity, which can be used in pharmaceutical compositions to treat or prevent diseases by administering therapeutically effective amounts to subjects in need.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing PARP1 inhibitors are used to treat BRCA1/2-deficient cancer cells, then cancer cell viability is disrupted through inhibition of DNA SSB repair, but cancer cells with alternative repair mechanisms remain viable
Solution Approach 1:
The patent converts the harmful effect of genome instability and alternative repair pathway activation into a benefit by specifically targeting and inactivating RAD52, which is essential for the alternative HR sub-pathway. This transforms the cancer cells' adaptive response (activating alternative repair) into a vulnerability that can be exploited for selective killing.
Solution Approach 2:
The patent changes the therapeutic parameter from inhibiting PARP1 (which affects SSB repair) to inhibiting RAD52 (which affects DSB repair through the alternative HR sub-pathway). This parameter change targets a different repair mechanism that is specifically essential for BRCA1/2-deficient cells, thereby overcoming resistance to PARP1 inhibitors.
2Reliability
If RAD52 is inactivated in BRCA1/2-deficient cells, then cancer cell viability is eliminated, but normal cells with functional BRCA1/2 remain unaffected
Solution Approach 1:
The patent applies local quality by designing a RAD52 inhibitor that specifically targets cells with BRCA1/2 deficiency. Normal cells with functional BRCA1/2 do not rely on the RAD52-dependent alternative HR sub-pathway and thus remain unaffected, creating a localized therapeutic effect specifically in the vulnerable cancer cell population.
Solution Approach 2:
The patent uses RAD52 as an intermediary target that mediates the difference in vulnerability between BRCA1/2-deficient cancer cells and normal cells. By targeting RAD52, the therapy exploits the intermediate repair pathway that is essential for cancer cells but redundant in normal cells, thereby achieving selective toxicity.
3Reliability
If the alternative HR sub-pathway dependent on RAD52 is inhibited, then BRCA1/2-deficient and PALB2-deficient cells become non-viable, but normal cells maintain viability through the major HR sub-pathway
Solution Approach 1:
The patent extracts and isolates the RAD52-dependent alternative HR sub-pathway from the complex network of DNA repair pathways. By specifically targeting RAD52, the therapy separates the essential repair function in BRCA1/2-deficient cells from the redundant repair functions in normal cells, simplifying the therapeutic strategy despite the underlying pathway complexity.
Data Source
AI summary
The present disclosure related to compounds of Formula I and Formula I and to their pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating RAD52 activity and may be used in the treatment of disorders in which RAD52 activity is implication, such as a cancer.