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
Pharmacology & Pharmacy
Yu Li, Yuanyuan Zhao, Xiaona Li, Liuqun Zhai, Hua Zheng, Ying Yan, Qiang Fu, Jinlian Ma, Haier Fu, Zhenqiang Zhang, Zhonghua Li
Summary: Alzheimer's disease is a common neurodegenerative disease with no cure. Lysine-specific demethylase 1 (LSD1) plays an important role in the pathogenesis of AD and has potential therapeutic benefits for treatment.
FRONTIERS IN PHARMACOLOGY
(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)
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)
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
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)
Review
Pharmacology & Pharmacy
Beatrice Noce, Elisabetta Di Bello, Rossella Fioravanti, Antonello Mai
Summary: Histone lysine-specific demethylase 1 (LSD1/KDM1A) is an epigenetic enzyme that demethylates specific lysine residues of histone H3. Its overexpression is associated with various cancers and leads to cellular-level effects such as differentiation block and increased proliferation, migration, and invasiveness. There are covalent and non-covalent LSD1 inhibitors, some of which are currently in clinical trials for cancer treatment. This review summarizes the structure and functions of LSD1, its pathological implications, and the development of LSD1 inhibitors as potential anticancer agents.
FRONTIERS IN PHARMACOLOGY
(2023)
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
Rossella Fioravanti, Veronica Rodriguez, Jonatan Caroli, Ugo Chianese, Rosaria Benedetti, Elisabetta Di Bello, Beatrice Noce, Clemens Zwergel, Davide Corinti, Dolores Vina, Lucia Altucci, Andrea Mattevi, Sergio Valente, Antonello Mai
Summary: In this study, a series of (hetero)arylbenzoylamino TCP derivatives were synthesized and evaluated for their biological activity. The results showed that the meta derivatives were more effective than the para analogues in inhibiting LSD1-CoREST activity, with the meta thienyl analogs 4b and 5b being the most potent. In cell-based assays, selected compounds displayed cell growth arrest mainly in prostate cancer LNCaP cells, confirming the involvement of LSD1 inhibition.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2022)
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
Chemistry, Medicinal
Canhui Zheng, Rohan Kalyan Rej, Mi Wang, Liyue Huang, Ester Fernandez-Salas, Chao-Yie Yang, Shaomeng Wang
Summary: In this study, a new class of highly potent and reversible LSD1 inhibitors, pyrrolo[2,3-c]pyridines, were discovered. Compound 46 showed significant inhibition of LSD1 enzymatic activity and cell growth, making it a promising lead compound for further optimization.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Plant Sciences
Laura Poza-Viejo, Miriam Paya-Milans, Patxi San Martin-Uriz, Laura Castro-Labrador, David Lara-Astiaso, Mark D. Wilkinson, Manuel Pineiro, Jose A. Jarillo, Pedro Crevillen
Summary: Epigenetic regulation is crucial for optimal development and maintenance of gene expression profiles. This study uncovers the epigenetic mechanisms involved in flowering time regulation in Brassica rapa, shedding light on the conserved and distinct regulatory mechanisms between model and crop species.
PLANT CELL AND ENVIRONMENT
(2022)
Article
Cell Biology
Baoyu Chen, Yuwen Zhu, Junliang Chen, Yifei Feng, Yong Xu
Summary: This study reveals that differential TCL expression in malignant colorectal cancer cells is associated with histone H3K9 methylation, and the lysine demethylase KDM4B is essential for TCL transcription. KDM4B interacts with the transcription factor ERG1 to activate TCL transcription by facilitating the assembly of pre-initiation complex on the TCL promoter, ultimately influencing migration and invasion of CRC cells. Additionally, upregulation of KDM4B in advanced stage CRC specimens suggests it may serve as a potential therapeutic target for CRC intervention.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Cell Biology
Ziyu Zhang, Baoyu Chen, Yuwen Zhu, Tianyi Zhang, Yibiao Yuan, Xiaoling Zhang, Yong Xu
Summary: TGF-beta regulates the transcription of the prometastatic small GTPase RHOJ by activating MKL1 and recruiting the H3K9/H3K27 dual demethylase KDM7A. KDM7A can be used to predict prognosis in breast cancer patients and its knockdown attenuates migration, invasion, growth, and metastasis of breast cancer cells. KDM7A is a direct transcriptional target of TGF-beta signaling, and small-molecule inhibitors of KDM7A may provide therapeutic solutions for malignant breast cancers.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Article
Clinical Neurology
Zeynab Alshelh, Ludovica Brusaferri, Atreyi Saha, Erin Morrissey, Paulina Knight, Minhae Kim, Yi Zhang, Jacob M. Hooker, Daniel Albrecht, Angel Torrado-Carvajal, Michael S. Placzek, Oluwaseun Akeju, Julie Price, Robert R. Edwards, Jeungchan Lee, Roberta Sclocco, Ciprian Catana, Vitaly Napadow, Marco L. Loggia
Summary: This study suggests that patients with different chronic pain conditions exhibit neuroinflammation, which is accompanied by neurophysiological changes and correlates with clinical presentation. These findings contribute to the subtyping of distinct pain syndromes and provide potential targets for precision medicine.
Article
Radiology, Nuclear Medicine & Medical Imaging
Bart de Laat, Yvonne E. Kling, Gwen Schroyen, Maarten Ooms, Jacob M. Hooker, Guy Bormans, Koen Van Laere, Jenny Ceccarini
Summary: This study demonstrates that chronic voluntary alcohol consumption leads to reversible increases in PDE10A enzymatic availability in the striatum, which is related to the amount of alcohol preference. The decrease in striatal PDE10A is associated with alcohol consumption and preference, and PDE10A inhibition may have beneficial effects on reducing alcohol intake.
EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING
(2022)
Review
Neurosciences
Chieh-En Jane Tseng, Christopher J. McDougle, Jacob M. Hooker, Nicole R. Zurcher
Summary: The etiology of autism spectrum disorder (ASD) remains unknown, but gene-environment interactions, mediated through epigenetic mechanisms, are thought to be a key contributing factor. Prenatal environmental factors have been shown to be associated with both increased risk of ASD and altered histone deacetylases (HDACs) or acetylation levels. Alterations in histone acetylation, which lead to changes in gene transcription, may play a key role in ASD.
BIOLOGICAL PSYCHIATRY
(2022)
Article
Clinical Neurology
Yuen-Siang Ang, Cristina Cusin, Yoann Petibon, Daniel G. Dillon, Micah Breiger, Emily L. Belleau, Marc Normandin, Hans Schroder, Sean Boyden, Emma Hayden, M. Taylor Levine, Aava Jahan, Ashley K. Meyer, Min Su Kang, Devon Brunner, Steven E. Gelda, Jacob Hooker, Georges El Fakhri, Maurizio Fava, Diego A. Pizzagalli
Summary: This study investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil on option generation in healthy individuals. The findings showed that patients with major depressive disorder generated fewer but more unique options, and dopamine activity in the putamen played a key role in option generation. Modafinil was also found to reduce the creativity of options produced by healthy individuals.
Article
Neurosciences
Tiziana Petrozziello, Evan A. Bordt, Alexandra N. Mills, Spencer E. Kim, Ellen Sapp, Benjamin A. Devlin, Abigail A. Obeng-Marnu, Sali M. K. Farhan, Ana C. Amaral, Simon Dujardin, Patrick M. Dooley, Christopher Henstridge, Derek H. Oakley, Andreas Neueder, Bradley T. Hyman, Tara L. Spires-Jones, Staci D. Bilbo, Khashayar Vakili, Merit E. Cudkowicz, James D. Berry, Marian DiFiglia, M. Catarina Silva, Stephen J. Haggarty, Ghazaleh Sadri-Vakili
Summary: Research suggests that increased levels of hyperphosphorylated tau may lead to mitochondrial fragmentation and oxidative stress in amyotrophic lateral sclerosis (ALS); reducing tau levels could potentially alleviate mitochondrial dysfunction in ALS.
MOLECULAR NEUROBIOLOGY
(2022)
Article
Cell Biology
Alexander K. Hafez, Amber J. Zimmerman, Grigorios Papageorgiou, Jayapriya Chandrasekaran, Stephen K. Amoah, Rixing Lin, Evelyn Lozano, Caroline Pierotti, Michela Dell'Orco, Brigham J. Hartley, Begum Alural, Jasmin Lalonde, John Matthew Esposito, Sabina Berretta, Alessio Squassina, Caterina Chillotti, Georgios Voloudakis, Zhipin Shao, John F. Fullard, Kristen J. Brennand, Gustavo Turecki, Panos Roussos, Roy H. Perlis, Stephen J. Haggarty, Nora Perrone-Bizzozero, Jonathan L. Brigman, Nikolaos Mellios
Summary: In this study, the researchers found that circHomer1 is inversely associated with HOMER1B mRNA levels in the brains of individuals with psychiatric disorders. They also demonstrated that circHomer1 knockdown inhibits the synaptic expression of Homer1b mRNA, while Homer1b knockdown increases synaptic circHomer1 levels and improves behavioral flexibility. Moreover, the combined knockdown of circHomer1 and Homer1b completely rescues the alterations in learning and synaptic gene expression associated with circHomer1.
Article
Biochemistry & Molecular Biology
Daniel M. Fass, Michael C. Lewis, Rushdy Ahmad, Matthew J. Szucs, Qiangge Zhang, Morgan Fleishman, Dongqing Wang, Myung Jong Kim, Jonathan Biag, Steven A. Carr, Edward M. Scolnick, Richard T. Premont, Stephen J. Haggarty
Summary: This study aims to elucidate the molecular and cellular basis of cognitive deficits in schizophrenia. The research found that genetic variations in a set of genes involved in regulating neuroplasticity may contribute to cognitive deficits and exert their effects by perturbing the networks of these genes.
MOLECULAR PSYCHIATRY
(2022)
Editorial Material
Chemistry, Medicinal
Courtney C. Aldrich, Felix Calderon, Stuart J. Conway, Chuan He, Jacob M. Hooker, Donna M. Huryn, Craig W. Lindsley, Dennis C. Liotta, Christa E. Muller
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Correction
Multidisciplinary Sciences
Tharick A. Pascoal, Mira Chamoun, Elad Lax, Hsiao-Ying Wey, Monica Shin, Kok Pin Ng, Min Su Kang, Sulantha Mathotaarachchi, Andrea L. Benedet, Joseph Therriault, Firoza Z. Lussier, Frederick A. Schroeder, Jonathan M. DuBois, Baileigh G. Hightower, Tonya M. Gilbert, Nicole R. Zurcher, Changning Wang, Robert Hopewell, Mallar Chakravarty, Melissa Savard, Emilie Thomas, Sara Mohaddes, Sarah Farzin, Alyssa Salaciak, Stephanie Tullo, A. Claudio Cuello, Jean-Paul Soucy, Gassan Massarweh, Heungsun Hwang, Eliane Kobayashi, Bradley T. Hyman, Bradford C. Dickerson, Marie-Christine Guiot, Moshe Szyf, Serge Gauthier, Jacob M. Hooker, Pedro Rosa-Neto
NATURE COMMUNICATIONS
(2022)
Editorial Material
Chemistry, Medicinal
Courtney C. Aldrich, Felix Calderon, Stuart J. Conway, Chuan He, Jacob M. Hooker, Donna M. Huryn, Craig W. Lindsley, Dennis C. Liotta, Christa E. Muller
Summary: Epigenetics is one of the fastest growing and most impactful fields in chemical biology, neuroscience, medicinal chemistry, and drug discovery. To highlight its importance, we invited submissions for a virtual special issue on this topic and present the Epigenetics 2022 virtual special issue.
ACS INFECTIOUS DISEASES
(2022)
Article
Biochemistry & Molecular Biology
Nicole D. Bartolo, Sarah E. Reid, Hema S. Krishnan, Azra Haseki, Muthukrishnan Renganathan, Tally M. Largent-Milnes, Braxton A. Norwood, Marco L. Loggia, Jacob M. Hooker
Summary: Voltage-gated sodium channels (Navs) play a crucial role in neuronal electrical signaling. This study used Radiocaine to visualize changes in neuronal Nav expression after neuropathic injury. The imaging results showed significantly higher uptake of Radiocaine in the injured sciatic nerve compared to the uninjured nerve, suggesting that Radiocaine could serve as a novel diagnostic tool for neuropathic pain conditions using PET imaging.
ACS CHEMICAL NEUROSCIENCE
(2022)
Editorial Material
Biochemistry & Molecular Biology
Jacob M. Hooker
ACS CHEMICAL NEUROSCIENCE
(2023)
Editorial Material
Biochemistry & Molecular Biology
Khalyd J. Clay, Ava E. Axelrod, Christina M. MacLaughlin, Jacob M. Hooker
Summary: Several naturally occurring molecules with potential in treating psychiatric illnesses, including entheogens, are being actively pursued in therapeutic development. However, the label of "DARK Classics" used in ACS Chemical Neuroscience may perpetuate harmful labels and stigmas. This Viewpoint aims to reframe the language surrounding entheogens and psychedelics to highlight their cultural history and uses.
ACS CHEMICAL NEUROSCIENCE
(2023)
Article
Multidisciplinary Sciences
Ping-Chieh Pao, Jinsoo Seo, Audrey Lee, Oleg Kritskiy, Debasis Patnaik, Jay Penney, Ravikiran M. Raju, Ute Geigenmuller, M. Catarina Silva, Diane E. Lucente, James F. Gusella, Bradford C. Dickerson, Anjanet Loon, Margaret X. Yu, Michael Bula, Melody Yu, Stephen J. Haggarty, Li-Hue Tsai
Summary: In this study, a 12-amino-acid-long peptide fragment derived from Cdk5 (Cdk5i) was identified. The Cdk5i showed high binding affinity toward the Cdk5/p25 complex and reduced Cdk5/p25 kinase activity, offering therapeutic potential for neurodegenerative diseases associated with Cdk5 hyperactivity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Editorial Material
Biochemistry & Molecular Biology
Rachel Wallace, David E. Olson, Jacob M. Hooker
Summary: Neuroplasticity is a complex concept that describes how the brain changes in response to various stimuli and its effects on human behavior. This viewpoint examines neuroplasticity from multiple perspectives to provide a comprehensive understanding of this ambiguous term. By highlighting its relevance in both health and disease, it emphasizes the significance of neuroplasticity in chemical neuroscience.
ACS CHEMICAL NEUROSCIENCE
(2023)