Synthesis of improved lysomotropic autophagy inhibitors
Tong Wang1, Megan L Goodall2,3, Paul Gonzales1
1†Translational Drug Development (TD2, LLC), Scottsdale, Arizona 85259, United States.
Abstract:
Autophagy is a conserved cellular pathway used to recycle nutrients through lysosomal breakdown basally and under times of stress (e.g., nutrient deprivation, chemotherapeutic treatment). Oncogenes are known to induce autophagy, which may be exploited by cancers for cell survival. To identify autophagy inhibitors with potential therapeutic value for cancer, we screened a panel of antimalarial agents and found that quinacrine (QN) had 60-fold higher potency of autophagy inhibition than chloroquine (CQ), a well-known autophagy inhibitor that functions by disrupting lysosomal activity. Despite desirable autophagy inhibiting properties, QN showed considerable cytotoxicity. Therefore, we designed and synthesized a novel series of QN analogs and investigated their effects on autophagy inhibition and cell viability. Notably, we found two compounds (33 and 34), bearing a backbone of 1,2,3,4-tetrahydroacridine, had limited cytotoxicity yet strong autophagy inhibition properties. In conclusion, these improved lysomotropic autophagy inhibitors may have use as anticancer agents in combination with conventional therapies.
Insights
Researchers identified novel quinacrine analogs that inhibit autophagy with low cytotoxicity. These compounds show potential as anticancer agents, especially when combined with existing therapies.
Area of Science:
- Cell Biology
- Cancer Research
- Medicinal Chemistry
Background:
- Autophagy is a cellular recycling process crucial for nutrient balance and stress response.
- Cancer cells exploit autophagy for survival, making it a therapeutic target.
- Antimalarial agents are explored for their autophagy-inhibiting potential.
Purpose of the Study:
- To identify potent autophagy inhibitors with therapeutic potential for cancer treatment.
- To synthesize and evaluate novel quinacrine analogs for improved efficacy and reduced toxicity.
Main Methods:
- Screening of antimalarial agents for autophagy inhibition.
- Synthesis of novel quinacrine analogs.
- Assessment of autophagy inhibition and cytotoxicity of compounds.
Main Results:
- Quinacrine (QN) demonstrated 60-fold higher autophagy inhibition potency than chloroquine (CQ).
- QN exhibited significant cytotoxicity, limiting its therapeutic use.
- Two novel analogs (33 and 34) based on 1,2,3,4-tetrahydroacridine showed potent autophagy inhibition with limited cytotoxicity.
Conclusions:
- Novel tetrahydroacridine-based compounds are effective lysomotropic autophagy inhibitors.
- These compounds offer a promising therapeutic strategy for cancer, particularly in combination therapies.
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