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Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors
Yue-Yang Ji1, Sen-Dong Lin1, Yu-Jie Wang2
1East China Normal University, Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, 3663 North Zhongshan Road, Shanghai, 200062, China.
Abstract:
Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials. However, thus far the majority of structure-activity relationship studies reported on these TCP derivatives have been mostly limited to the racemates. In this study, we present the SAR data for a novel series of conformationally-restricted TCP-based LSD1 inhibitors, both in their racemic and enantiomerically pure forms. Compounds 18b and 19b were identified as the most potent LSD1 inhibitors within this series, possessing excellent selectivity (>10,000-fold) against MAO-A and MAO-B. These compounds activated CD86 expression on the human MV4-11 AML cells following 10 days of exposure, accompanied with the apparent cytotoxicity. Taken together, these findings are consistent with the pharmacological inhibition of LSD1 and further provide structural insights on the binding modes of these TCP derivatives and their enantiomers at the LSD1.
Insights
Novel Tranylcypromine (TCP) derivatives were developed as potent lysine-specific histone demethylase 1 (LSD1) inhibitors. These compounds show high selectivity against MAO-A/B and exhibit anti-cancer activity in AML cells.
Area of Science:
- Medicinal Chemistry
- Oncology
- Biochemistry
Background:
- Aberrant lysine-specific histone demethylase 1 (LSD1) expression is linked to various cancers, positioning it as a potential therapeutic target.
- Tranylcypromine (TCP), an established antidepressant, targets monoamine oxidases (MAO-A/B) and shares structural similarities with LSD1.
- Existing structure-activity relationship (SAR) studies on TCP-based LSD1 inhibitors often focus on racemates, limiting enantiomeric insights.
Purpose of the Study:
- To investigate the structure-activity relationships (SAR) of novel, conformationally-restricted TCP-based LSD1 inhibitors.
- To evaluate both racemic and enantiomerically pure forms of these inhibitors.
- To assess the selectivity and anti-cancer effects of potent LSD1 inhibitors.
Main Methods:
- Synthesis of a novel series of conformationally-restricted TCP derivatives.
- Evaluation of LSD1 inhibitory activity and selectivity against MAO-A and MAO-B.
- Assessment of CD86 expression and cytotoxicity in MV4-11 AML cells.
Main Results:
- Compounds 18b and 19b emerged as highly potent LSD1 inhibitors.
- These compounds demonstrated exceptional selectivity (>10,000-fold) over MAO-A and MAO-B.
- Treatment with 18b and 19b activated CD86 expression and induced cytotoxicity in MV4-11 AML cells.
Conclusions:
- The developed TCP derivatives are effective LSD1 inhibitors with significant anti-cancer potential.
- The study provides valuable structural insights into the binding of TCP derivatives and their enantiomers to LSD1.
- These findings support the pharmacological inhibition of LSD1 as a viable anti-cancer strategy.