Review
Chemistry, Medicinal
Yihui Song, Huiqing Zhang, Xiaoke Yang, Yuting Shi, Bin Yu
Summary: Lysine-specific demethylase 1 (LSD1/KDM1A) has emerged as a promising epigenetic target for disease treatment. This review provides an update on LSD1 inhibitors, including natural products, synthetic compounds, and cyclic peptides reported in 2021. The design strategies, structure-activity relationships, binding model analysis, and modes of action are discussed. Highlights include the repurposing of FDA-approved drugs as reversible LSD1 inhibitors, the identification of clinical candidates for neuro-developmental disorders, and the enhanced anti-cancer effects of dual inhibitors targeting both LSD1 and HDAC6 or tubulin.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Dong-Jun Fu, Jun Li, Bin Yu
Summary: This review highlights the research progress of LSD1 inhibitors, categorizing them into natural and synthetic compounds. The potential of these inhibitors in cancer treatment, as well as related design strategies, are discussed.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Cell Biology
Annamaria Antona, Giovanni Leo, Francesco Favero, Marco Varalda, Jacopo Venetucci, Stefania Faletti, Matilde Todaro, Eleonora Mazzucco, Enrica Soligo, Chiara Saglietti, Giorgio Stassi, Marcello Manfredi, Giuliana Pelicci, Davide Cora, Guido Valente, Daniela Capello
Summary: Colorectal cancer (CRC) is the 3rd most common cancer and the 2nd leading cause of death worldwide. Cancer stem cells (CSCs), which are highly resistant to therapy and responsible for tumor relapse, require new therapeutic strategies. Upregulated expression of KDM1A has been found in various tumors and is associated with poor prognosis due to its role in maintaining CSCs. Inhibiting KDM1A can significantly decrease self-renewal, migration, and invasion potential in CRC-SCs, and impact CRC progression in multiple ways, making it a promising epigenetic target for preventing tumor relapse.
CELL DEATH DISCOVERY
(2023)
Review
Cell Biology
Harinder Gill
Summary: Myelofibrosis is the most severe form of myeloproliferative neoplasm and currently only allogeneic hematopoietic stem cell transplantation has the potential for cure, but with high mortality and morbidity. JAK inhibition is the main treatment for intermediate- and high-risk MF, and Ruxolitinib is the most commonly used JAK1/2 inhibitor with durable effects in controlling symptoms and spleen volumes. However, Ruxolitinib may not address the underlying disease biology effectively.
Article
Multidisciplinary Sciences
Mattie J. Casey, Alexandra M. Call, Annika V. Thorpe, Cicely A. Jette, Michael E. Engel, Rodney A. Stewart
Summary: Lsd1/Kdm1a functions as both a histone demethylase enzyme and a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression during embryogenesis. Our analysis of zebrafish lsd1/kdm1a mutants reveals that Lsd1's scaffolding function, mediated by its SNAG-binding domain, is required for repression of gene expression, including gfi1 and snai1/2, through a negative feedback loop.
Article
Immunology
Jingjing Wang, Zhikai Wu, Xingyi Zhu, Peixuan Li, Yiwu Fu, Xia Wang, Youpeng Sun, Ershun Zhou, Zhengtao Yang
Summary: The study demonstrates the important regulatory roles of LSD1 in LPS-induced mastitis and the inhibitory effects of GSK-LSD1 on LSD1 activity, leading to reduced inflammatory response and tissue damage. The inhibition of LSD1 results in increased histone H3K4me2 and H3K9me2 levels, and suppression of NF-kappa B signaling and cytokine production in mammary gland. These findings suggest LSD1 as a potential regulator of inflammation and provide insights into epigenetic control mechanisms in inflammation.
INTERNATIONAL IMMUNOPHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Chao Yang, Yuan Fang, Xiang Luo, Dehong Teng, Zhongqiu Liu, Yingtang Zhou, Guochao Liao
Summary: FY-56 is a highly potent and selective LSD1 inhibitor that can inhibit the proliferation of leukemia cells and induce differentiation, showing therapeutic potential for AML treatment.
BIOORGANIC CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Martina Menna, Francesco Fiorentino, Biagina Marrocco, Alessia Lucidi, Stefano Tomassi, Domenica Cilli, Mauro Romanenghi, Matteo Cassandri, Silvia Pomella, Michele Pezzella, Donatella Del Bufalo, Mohammad Salik Zeya Ansari, Nevena Tomasevic, Milan Mladenovic, Monica Viviano, Gianluca Sbardella, Rossella Rota, Daniela Trisciuoglio, Saverio Minucci, Andrea Mattevi, Dante Rotili, Antonello Mai
Summary: Chemical modifications of LSD1 led to highly active and selective inhibitors, which showed antiproliferative effects and gene expression regulation in leukemia cells. The inhibition of LSD1 demonstrated a crucial role in solid tumor cells, suggesting no added value for simultaneous G9a inhibition.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xing-Jie Dai, Ying Liu, Lei-Peng Xue, Xiao-Peng Xiong, Ying Zhou, Yi-Chao Zheng, Hong-Min Liu
Summary: LSD1, a FAD-dependent monoamine oxidase, functions as a transcription coactivator or corepressor to regulate histone methylation, and has emerged as a promising epigenetic target for anticancer treatment. Numerous inhibitors targeting LSD1 have been developed, with some undergoing clinical trials for cancer therapy. Significant advances have been made in the development of reversible LSD1 inhibitors over the past decade.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Oncology
Jinzhong Chen, Chengiang Yang, Ye Yang, Qingyang Liang, Kegong Xie, Jia Liu, Yujin Tang
Summary: The study found significantly increased expression of DKK1 in alcohol-induced ONFH, suggesting its role in disease progression by inhibiting the Wnt/beta-catenin signaling pathway. Targeting DKK1 to activate this pathway may be an effective therapeutic strategy to prevent ONFH.
AMERICAN JOURNAL OF TRANSLATIONAL RESEARCH
(2021)
Article
Chemistry, Medicinal
Catherine M. Mills, Jonathan Turner, Ivett C. Pina, Kathleen A. Garrabrant, Dirk Geerts, Andre S. Bachmann, Yuri K. Peterson, Patrick M. Woster
Summary: LSD1, an epigenetic regulator, is an oncogenic accomplice in MYCN-expressing neuroblastoma. We report 3 novel scaffolds for reversible LSD1 inhibition and found one of them to be highly potent and able to increase an important modification mark in cells. Combination treatment with bortezomib also showed a synergistic effect.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Irina Giralt, Gabriel Gallo-Oller, Natalia Navarro, Patricia Zarzosa, Guillem Pons, Ainara Magdaleno, Miguel F. Segura, Constantino Sabado, Raquel Hladun, Diego Arango, Jose Sanchez de Toledo, Lucas Moreno, Soledad Gallego, Josep Roma
Summary: The study demonstrates the therapeutic potential of DKK-1 pharmaceutical inhibition in rhabdomyosarcoma, resulting in beta-catenin activation and modulation of focal adhesion kinase, with positive effects on myogenic marker expression and a reduction in proliferation and invasion. In addition, the chemical inhibitor WAY-262611 was able to impair tumor cell survival in vivo, suggesting DKK-1 as a potential molecular target for novel therapeutic strategies in RMS patients, especially those with high DKK-1 expression.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)
Review
Cell Biology
Dimitri Papukashvili, Nino Rcheulishvili, Cong Liu, Fengfei Xie, Deependra Tyagi, Yunjiao He, Peng George Wang
Summary: Androgenetic alopecia (AGA) is a challenging issue that requires the development of new treatment methods. The Wnt/β-catenin signaling pathway is crucial for hair growth and can be targeted for AGA therapy.
Article
Cell Biology
Georgia Papadopoulou, Stavroula Petroulia, Eirini Karamichali, Alexios Dimitriadis, Dimitrios Marousis, Elisavet Ioannidou, Panagiota Papazafiri, John Koskinas, Pelagia Foka, Urania Georgopoulou
Summary: Hepatitis C virus (HCV) alters gene expression epigenetically to rearrange the cellular microenvironment in a beneficial way for its life cycle. Lysine-specific demethylase 1 (LSD1) is an epigenetic controller of critical cellular functions that are essential for HCV propagation. This study investigates the role of LSD1 in HCV infection and shows that LSD1 overexpression inhibits HCV replication, while inhibition of LSD1 increases viral replication. The study also suggests that LSD1 participates in an antiviral mechanism by activating IFITM3 via demethylation, leading to degradation of HCV virions.
Article
Anatomy & Morphology
Chunyi Ji, Lijian Chen, Miaoxian Yuan, Weixin Xie, Xinyi Sheng, Qiang Yin
Summary: This study investigates the mechanism of KDM1A-regulated hepatoblastoma (HB) development. The expression levels of KDM1A and DKK3 were analyzed in HB patients, and experiments were conducted on cell lines and nude mice to study the effects of knockdown of KDM1A and DKK3. The results suggest that KDM1A stimulates HB development by activating the Wnt/beta-catenin pathway through inhibition of DKK3 transcription.
