Tying up tranylcypromine: Novel selective histone lysine specific demethylase 1 (LSD1) inhibitors
| Autor: | Wei Zhang, Fan Yang, Hendra Gunosewoyo, Yubo Zhou, Li-Fang Yu, Sen-Dong Lin, Ji Yueyang, Jie Tang, Mingbo Su, Wang Yujie, Jia Li |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
animal structures Druggability Antineoplastic Agents Pharmacology 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Drug Discovery medicine Structure–activity relationship Humans Enzyme Inhibitors Cytotoxicity Cell Proliferation Histone Demethylases biology Dose-Response Relationship Drug Molecular Structure Chemistry Organic Chemistry Tranylcypromine General Medicine 030104 developmental biology Histone Biochemistry 030220 oncology & carcinogenesis biology.protein Monoamine oxidase B Monoamine oxidase A medicine.drug |
| Zdroj: | European journal of medicinal chemistry. 141 |
| ISSN: | 1768-3254 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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