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Tranylcypromine-derived LSD1 inhibitors: Synthetic strategies, structure-activity relationships, and anticancer
Khursheed Ahmad Sheikh1, Siddiqui Muzammil1, Elaf Raneem1
1Drug Design and Medicinal Chemistry Lab, Department of Pharmaceutical Chemistry, School of Pharmaceutical Education & Research, Jamia Hamdard, New Delhi, 110062, India.
Abstract:
Lysine-specific demethylase 1 (LSD1), frequently overexpressed in cancers, drives tumor progression by demethylating oncogenic histone marks H3K4me1/2 and H3K9me1/2, establishing it as a compelling therapeutic target. Inhibition of LSD1 suppresses cancer cell proliferation, invasion, and migration, prompting extensive development of inhibitors since its discovery. Tranylcypromine derivatives represent the most potent inhibitor class, exhibiting sub-micromolar to nanomolar IC50 values. Clinically evaluated candidates like TCP, ORY-1001, and INCB059872; administered alone or in combination; irreversibly inhibit LSD1 by binding its FAD cofactor. This review systematically analyzes all reported tranylcypromine-based LSD1 inhibitors, elucidating their structure-activity relationships (SAR), synthetic strategies, mechanistic insights, and anticancer profiles. Key SAR modifications enhancing potency and selectivity are highlighted. Collectively, these inhibitors demonstrate significant therapeutic promise. We further discuss challenges (e.g., selectivity, resistance), opportunities, and future directions for optimizing LSD1-targeted cancer therapies.
Insights
Tranylcypromine derivatives are potent inhibitors of Lysine-specific demethylase 1 (LSD1), a key driver in cancer progression. This review details their structure-activity relationships and therapeutic potential for cancer treatment.
Area of Science:
- Biochemistry
- Oncology
- Medicinal Chemistry
Background:
- Lysine-specific demethylase 1 (LSD1) is overexpressed in cancers, promoting tumor growth by altering histone methylation.
- LSD1 inhibition is a promising therapeutic strategy, with tranylcypromine derivatives showing high potency.
Purpose of the Study:
- To systematically review tranylcypromine-based LSD1 inhibitors.
- To elucidate their structure-activity relationships (SAR), synthesis, mechanisms, and anticancer effects.
Main Methods:
- Comprehensive literature analysis of tranylcypromine-derived LSD1 inhibitors.
- Evaluation of SAR, synthetic routes, and mechanistic data.
- Assessment of preclinical and clinical anticancer profiles.
Main Results:
- Tranylcypromine derivatives exhibit potent, irreversible LSD1 inhibition with sub-micromolar to nanomolar IC50 values.
- Key SAR modifications enhance inhibitor potency and selectivity.
- Clinically evaluated candidates (TCP, ORY-1001, INCB059872) demonstrate significant anticancer activity.
Conclusions:
- Tranylcypromine-based LSD1 inhibitors show considerable therapeutic promise for cancer treatment.
- Further optimization is needed to address challenges like selectivity and resistance.
- Future research should focus on refining these inhibitors for enhanced efficacy.
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