Mcl-1 Inhibitors Enhance DNA Replication Stress Sensitivity
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Solution Overview
Problem
Current cancer therapies, such as radiation and chemotherapy, often induce DNA double-strand breaks that can lead to genomic instability due to inappropriate repair, and non-small cell lung cancer is particularly challenging to treat effectively.
Innovation Solution
Development of compounds that inhibit Mcl-1-stimulated homologous recombination (HR) DNA repair, specifically targeting the Mcl-1 BH1 domain, in combination with agents like hydroxyurea or olaparib, to enhance sensitivity to DNA replication stress and cancer therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If radiation and chemotherapy are used to treat lung cancer, then cancer cells are damaged, but DNA double-strand breaks lead to genomic instability due to inappropriate repair
Solution Approach 1:
Mcl-1 acts as an intermediary protein that mediates the interaction between DNA damage response pathways and repair mechanisms. By targeting Mcl-1 with selective inhibitors, the patent modulates the repair process to favor accurate homologous recombination over error-prone non-homologous end joining, thereby reducing genomic instability while maintaining cancer cell killing efficacy
Solution Approach 2:
The patent changes the parameter of DNA repair pathway selection by modulating Mcl-1 protein levels and activity. This shifts the repair mechanism from inappropriate non-homologous end joining to appropriate homologous recombination repair, improving the quality of DNA repair and reducing genomic instability in cancer cells treated with radiation and chemotherapy
2Reliability
If Mcl-1 is inhibited to sensitize cancer cells to therapy, then cancer cell survival decreases, but normal cells may also be affected
Solution Approach 1:
The patent exploits local quality differences in Mcl-1 expression and function between cancer cells and normal cells. Cancer cells, particularly those with high Mcl-1 expression driven by oncogenic pathways, are selectively sensitized to therapy by Mcl-1 inhibition, while normal cells with lower or differently regulated Mcl-1 levels are relatively protected, reducing side effects
3Productivity
If DNA repair pathways are modulated to improve treatment efficacy, then cancer progression is controlled, but repair mechanisms may become inappropriate leading to mutations
Solution Approach 1:
The patent utilizes feedback mechanisms in DNA damage response pathways by targeting Mcl-1, which is regulated by DNA damage signaling. This creates a feedback loop where DNA damage induces Mcl-1 expression, which then modulates repair pathway selection, ensuring that repair is activated only when needed and directed toward appropriate mechanisms, preventing inappropriate repair and mutation accumulation
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively inhibit HR-mediated DNA repair, sensitizing cancer cells to DNA replication stress agents, leading to potent anti-tumor activity in lung cancer models both in vitro and in vivo, with reduced side effects.
Implementation Method 1
the compound that inhibits Mcl-1-stimulated homologous recombination DNA repair specifically binds with Mcl-1 BH1 domain (aa256-265)
Data Source
AI summary
This disclosure relates to inhibitors of Mcl-1 stimulated homologous recombination (HR) DNA repair and uses for treating cancer. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering an inhibitor of Mcl-1 in combination with other anti-cancer agents, e.g., that induce DNA replication stress. In certain embodiments, this disclosure relates to methods of treating cancer comprising administering compounds disclosed herein in combination with hydroxyurea, olaparib, or combinations thereof.