Natural products as LSD1 inhibitors for cancer therapy

Abstract

Natural products generally fall into the biologically relevant chemical space and always possess novel biological activities, thus making them a rich source of lead compounds for new drug discovery. With the recent technological advances, natural product-based drug discovery is now reaching a new era. Natural products have also shown promise in epigenetic drug discovery, some of them have advanced into clinical trials or are presently being used in clinic. The histone lysine specific demethylase 1 (LSD1), an important class of histone demethylases, has fundamental roles in the development of various pathological conditions. Targeting LSD1 has been recognized as a promising therapeutic option for cancer treatment. Notably, some natural products with different chemotypes including protoberberine alkaloids, flavones, polyphenols, and cyclic peptides have shown effectiveness against LSD1. These natural products provide novel scaffolds for developing new LSD1 inhibitors. In this review, we mainly discuss the identification of natural LSD1 inhibitors, analysis of the co-crystal structures of LSD1/natural product complex, antitumor activity and their modes of action. We also briefly discuss the challenges faced in this field. We believe this review will provide a landscape of natural LSD1 inhibitors.

Keywords: AML, acute myeloid leukemia; CCC, cut countercurrent chromatography; CD11b, integrin alpha M; CD14, cluster of differentiation 14; CD86, cluster of differentiation 86; COVID-19, coronavirus disease; Cancer therapy; CoREST, RE1-silencing transcription factor co-repressor; Drug discovery; EMT, epithelial–mesenchymal transition; EVOO, extra virgin olive oil; EdU, 5-ethynyl-20-deoxyuridine; Epigenetic regulation; FAD, flavin adenine dinucleotide; FDA, U.S. Food and Drug Administration; GGA, geranylgeranoic acid; H3K4, histone H3 lysine 4; H3K9, histone H3 lysine 9; HDAC, histone deacetylase; HRP, horseradish peroxidase; Histone demethylase; Kt, competitive inhibition constant; LSD1 inhibitors; LSD1, lysine-specific histone demethylase 1A; MAO-A, monoamine oxidase A; MHC, myosin heavy chain; MMA, methylmalonic acid; NAD, nicotinamide adenine dinucleotide; NTRK2, neurotrophic receptor tyrosine kinase 2; Natural products; PDX, patient-derived xenograft; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SARs, structure–activity relationship studies; SIRT1, sirtuin 1; SOX2, sex determining region Y-box 2; SPR, surface plasmon resonance; TCP, tranylcypromine; THF, tetrahydrofolate; Tm, melting temperature; iPS, induced pluripotent stem; mRNA, messenger RNA; siRNA, small interfering RNA; ΔΨm, mitochondrial transmembrane potential; α-MG, α-mangostin.