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)
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)
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
Chemistry, Medicinal
Xing-Jie Dai, Li-Juan Zhao, Long-Hua Yang, Ting Guo, Lei-Peng Xue, Hong-Mei Ren, Zhi-Li Yin, Xiao-Peng Xiong, Ying Zhou, Shi-Kun Ji, Hui-Min Liu, Hong-Min Liu, Ying Liu, Yi-Chao Zheng
Summary: In this study, the antipsychotic drug chlorpromazine was identified as an LSD1 inhibitor, and a series of chlorpromazine derivatives were synthesized. Among them, compound 3s showed the most potent inhibitory activity. Compound 3s inhibited LSD1 at the cellular level, downregulated PD-L1 expression in gastric cancer cells, and enhanced T-cell killing response. Animal studies confirmed that compound 3s can inhibit gastric cancer cell proliferation without significant toxicity in immunocompetent mice. These findings suggest that compound 3s may serve as a lead compound for further development to activate T-cell immunity in gastric cancer.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Pharmacology & Pharmacy
Yuan Fang, Chao Yang, Zhiqiang Yu, Xiaochuan Li, Qingchun Mu, Guochao Liao, Bin Yu
Summary: Natural products are an important source of lead compounds for drug discovery, showing promise in cancer treatment by targeting LSD1. Different chemotypes of natural products have been effective against LSD1, providing novel scaffolds for new inhibitors. This review discusses the identification of natural LSD1 inhibitors, their anti-tumor activities, and challenges faced in this field.
ACTA PHARMACEUTICA SINICA B
(2021)
Article
Multidisciplinary Sciences
Cheng Zeng, Jiwei Chen, Emmalee W. Cooke, Arijita Subuddhi, Eliana T. Roodman, Fei Xavier Chen, Kaixiang Cao
Summary: This study reveals the catalytic-independent role of LSD1 in regulating gene expression and cellular differentiation, demonstrating that the loss of LSD1 protein globally de-represses enhancers and impairs cell fate transition. The researchers found that the increase of H3K27ac catalyzed by P300/CBP, rather than the loss of CoREST complex components from chromatin, contributes to the transcription de-repression of LSD1 targets and differentiation defects caused by LSD1 loss.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Ming-Jie Huang, Jia-Wen Guo, Yun-Dong Fu, Ya-Zhen You, Wen-Yu Xu, Ting-Yu Song, Ran Li, Zi-Tong Chen, Li-Hua Huang, Hong-Min Liu
Summary: Structural modifications of Tranylcypromine (TCP) led to the discovery of new LSD1 inhibitors, with compounds 26b and 29b effectively inhibiting LSD1 and showing good selectivity over MAO-B. Mechanistic studies revealed that compound 29b induced accumulation of H3K4me1/2 in LSD1 overexpressed MGC-803 cells and inhibited metastasis of MGC803 cells. Overall, both compounds could serve as promising lead compounds for further investigation.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Pharmacology & Pharmacy
Baohui Yuan, He Liu, Xiaohua Pan, Xiaoliang Dong, Le-Feng Qu, Jia Sun, Li-Long Pan
Summary: LSD1 plays a crucial role in neointima formation, and its overexpression is associated with neointima formation. Knockdown of LSD1 significantly reduces neointima formation and inhibits platelet-derived growth factor-induced VSMC proliferation. Moreover, LSD1 overexpression exhibits opposite effects in vivo and in vitro.
BIOCHEMICAL PHARMACOLOGY
(2022)
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)
Review
Pharmacology & Pharmacy
Guan-Jun Yang, Yan-Jun Liu, Li-Jian Ding, Fan Tao, Ming-Hui Zhu, Zhen-Yuan Shi, Juan-Ming Wen, Meng-Yao Niu, Xiang Li, Zhan-Song Xu, Wan-Jia Qin, Chen-Jie Fei, Jiong Chen
Summary: This review provides a comprehensive overview of the role of LSD1 in breast cancer, its action mechanisms, the therapeutic potential of LSD1 inhibitors, and the current opportunities and challenges of targeting LSD1 for breast cancer therapy.
FRONTIERS IN PHARMACOLOGY
(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)
Review
Cell Biology
Carlos Martinez-Gamero, Sandhya Malla, Francesca Aguilo
Summary: This review summarizes the current knowledge about LSD1 and its molecular mechanism in influencing the stem cell state, including the regulatory circuitry underlying self-renewal and pluripotency.
Article
Biochemistry & Molecular Biology
Wei-Shiung Lian, Re-Wen Wu, Jih-Yang Ko, Yu-Shan Chen, Shao-Yu Wang, Holger Jahr, Feng-Sheng Wang
Summary: Loss of H3K27me3 demethylase Kdm6a function affects chondrocyte activity and mitigates the development of osteoarthritis. Kdm6a deletion changes gene expression, represses Wnt10a and Fzd10 transcription, and contributes to cartilage synthesis and protection. The use of Kdm6a inhibitor shows potential for treating osteoarthritic disorders.
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
(2023)
Article
Multidisciplinary Sciences
Chandru Gajendran, Subramanyam Janardhan Tantry, M. Naveen Sadhu, Zainuddin Mohammed, Purushottam Dewang, Mahanandeesha Hallur, Sreekala Nair, Krishnakumar Vaithilingam, Basavaprabhu Nagayya, Sridharan Rajagopal, Dhanalakshmi Sivanandhan
Summary: JBI-097, a dual LSD1/HDAC6 inhibitor, demonstrates strong inhibitory effects on tumor growth and anti-proliferative activity against both hematologic and solid tumor cell lines. It shows promising efficacy in erythroleukemia, multiple myeloma xenograft models, and CT-26 syngeneic model, and has additive or synergistic efficacy in combination with standard therapy or immune checkpoint inhibitors.
Article
Cell Biology
Yuechao Sun, Weipeng Gong, Song Zhang
Summary: The study revealed the dual role of METTL3 in colorectal cancer as both an m6A writer and a transcription regulator, working together in the same signaling pathway to drive the malignancy of colorectal cancer.
CELL DEATH & DISEASE
(2023)