BRCA1-BARD1 Inhibitor Compounds for Resistant BRCA-Deficient Cancers
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Solution Overview
Problem
Current targeted therapies for cancers associated with BRCA1/2 deficiencies, such as breast and ovarian cancers, face challenges with therapeutic resistance due to DNA damage repair pathway activation, necessitating more effective inhibitors to sensitize cancer cells to DNA-damaging agents.
Innovation Solution
Development of novel compounds that inhibit the BRCA1/2 pathway, particularly by disrupting the BRCA1-BARD1 interaction, leading to inhibition of homologous recombination DNA repair and sensitizing cancer cells to chemotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If PARP inhibitors are used to treat BRCA1-deficient cancers, then initial therapeutic response is good, but therapeutic resistance develops over time due to DNA damage repair pathway activation
Solution Approach 1:
The patent uses BARD1 protein as an intermediary target. Instead of directly inhibiting PARP enzymes, the compound disrupts the BRCA1-BARD1 interaction, which indirectly prevents homologous recombination repair. This intermediary approach creates a more effective blockade of DNA repair pathways, preventing resistance development while maintaining initial therapeutic response.
Solution Approach 2:
The invention changes the target parameter from PARP enzyme inhibition to BRCA1-BARD1 interaction disruption. By altering the molecular target and mechanism of action, the compound achieves sustained therapeutic effect without the resistance problems associated with PARP inhibitors. The compound specifically binds to BARD1 and prevents its interaction with BRCA1, fundamentally changing the approach to DNA repair inhibition.
2Productivity
If conventional chemotherapy is used to treat cancer, then cell death is induced in rapidly dividing cells, but toxicity to normal cells and side effects increase
Solution Approach 1:
The compound exhibits local quality by selectively affecting cancer cells with BRCA1/2 deficiencies while sparing normal cells. The mechanism targets a specific molecular defect (BRCA1-BARD1 interaction) that is present in cancer cells but not in healthy cells, creating localized therapeutic action at the molecular level. This specificity eliminates the need for broad-spectrum cytotoxicity that causes normal cell damage.
Solution Approach 2:
The invention converts the cancer cells' reliance on DNA repair pathways into a vulnerability. By disrupting the BRCA1-BARD1 interaction, the compound transforms the cells' repair capacity into a lethal weakness, causing accumulated DNA damage that leads to selective cancer cell death while leaving normal cells unaffected.
3Strength
If DNA damage repair pathways remain functional in cancer cells, then cell death from DNA-damaging agents is avoided, but therapeutic efficacy decreases
Solution Approach 1:
The compound performs preliminary action by preemptively disrupting the BRCA1-BARD1 interaction before DNA-damaging therapy is administered. This pre-blockade of the repair pathway ensures that when DNA damage occurs during chemotherapy or radiation, the cancer cells cannot repair the damage, leading to enhanced cell death. The repair pathway is inhibited in advance, preventing resistance.
Data Source
AI summary
The present disclosure relates to novel compounds according to general Formula I or a pharmaceutically acceptable acid or base addition salts, hydrate, solvate, N-oxide, stereo chemically isomer forms, in particular diastereoisomer, enantiomer or atropisomers, or mixtures thereof, a polymorph or ester thereof. The present disclosure also relates to a pharmaceutical composition comprising a compound or prodrug thereof of Formula I for use in the treatment of conditions influenced by homologous recombination DNA repair pathway and wild-type, mutant and other BRCA1 and/or BRCA2 deficiencies, namely therapy or treatment of cancer.