LSD1-based dual-target inhibitors as emerging anticancer agents: pharmacological perspectives and SAR exploration

Area of Science:

• Epigenetics and Molecular Biology
• Cancer Pharmacology
• Medicinal Chemistry

Background:

• Lysine-specific demethylase 1 (LSD1) is a crucial epigenetic enzyme regulating gene transcription.
• LSD1 overexpression is implicated in various cancers, including prostate, breast, lung, and leukemia.
• Current LSD1 inhibitors face limitations like low selectivity, toxicity, and drug resistance.

Purpose of the Study:

• To review recent design strategies and structure-activity relationships (SAR) for LSD1-based dual inhibitors.
• To explore the fusion of LSD1 pharmacophores with other heterocyclic and zinc-binding cores.
• To guide the development of novel dual inhibitors for enhanced cancer therapy.

Main Methods:

• Review of literature on LSD1 inhibitors and dual-targeting strategies.
• Analysis of pharmacophore fusion approaches combining LSD1 targeting moieties with other cores.
• Examination of SAR data for designed dual inhibitors.

Main Results:

• Successful design of dual inhibitors targeting LSD1 and partners like HDAC, EGFR, EZH2, and tubulin.
• Fusion strategies involve incorporating pharmacophores (e.g., tranylcypromine, indole) with cores (e.g., hydroxamic acids, bipyridine).
• These hybrid molecules demonstrate potential for inducing apoptosis and blocking cell-cycle progression.

Conclusions:

• Dual inhibition strategies offer a promising approach to overcome limitations of LSD1 monotherapy in cancer.
• Structural insights and SAR data are crucial for optimizing the design of effective LSD1-based dual inhibitors.
• Further development of these dual inhibitors holds potential for synergistic anticancer effects and improved therapeutic outcomes.