Article
Biochemistry & Molecular Biology
James E. Longbotham, Mark J. S. Kelly, Danica Galonic Fujimori
Summary: PHD reader domains are involved in recruiting protein complexes and are sensitive to the methylation state of histone H3, with the PHD1 domain of KDM5A playing a regulatory role when bound to the H3 tail. The structural details of H3 binding site in PHD1 could aid in the development of small molecule modulators of KDM5A.
ACS CHEMICAL BIOLOGY
(2021)
Article
Chemistry, Medicinal
Guan-Jun Yang, Jia Wu, Liang Miao, Ming-Hui Zhu, Qian-Jin Zhou, Xin-Jiang Lu, Jian-Fei Lu, Chung-Hang Leung, Dik-Lung Ma, Jiong Chen
Summary: KDM5A, a demethylase that is aberrantly expressed in many cancers, plays a role in promoting cancer cell proliferation, metastasis, invasiveness, drug resistance, and poor prognosis. Pharmacological inhibition of KDM5A has been shown to significantly attenuate tumor progression and may serve as a potential drug target in cancer therapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biotechnology & Applied Microbiology
Hong Wu, Lidong Xu, Xun Hu
Summary: This study found that KDM5A is upregulated in human lung adenocarcinoma and regulates the proliferation of cancer cells. Silencing KDM5A inhibits cell proliferation and induces apoptosis in lung adenocarcinoma cells, while also increasing their sensitivity to gefitinib.
Article
Biochemistry & Molecular Biology
Tianqi Wang, Yang Liu, Hailin Zhang, Zhen Fang, Rong Zhang, Wenqing Zhang, Yan Fan, Rong Xiang
Summary: Crystal complex structures of two KDM4D inhibitors, OWS and 10r, have been determined, offering new insights for rational design and optimization of KDM4D inhibitors.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2021)
Article
Cell Biology
Ramhari Kumbhar, Anthony Sanchez, Jullian Perren, Fade Gong, David Corujo, Frank Medina, Sravan K. Devanathan, Blerta Xhemalce, Andreas Matouschek, Marcus Buschbeck, Bethany A. Buck-Koehntop, Kyle M. Miller
Summary: This study uncovers the crucial factors involved in the recognition of DNA lesion sites by the histone demethylase KDM5A, including a noncanonical poly(ADP-ribose) binding region and the histone variant macroH2A1.2. These factors are essential for KDM5A's functions at DNA damage sites and play key roles in DNA repair processes.
JOURNAL OF CELL BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Lan Zhang, Yao Chen, Zhijia Li, Congcong Lin, Tongtong Zhang, Guan Wang
Summary: Histone methylation is a common and dynamic histone modification that regulates gene transcription by changing chromatin structure. Lysine demethylases play a vital role in maintaining epigenetic factors and are involved in various diseases, including cancer. Recent advancements have led to the discovery of inhibitors that disrupt lysine demethylation, particularly focusing on JmjC-domain-containing histone lysine demethylases (KDM2-7). This review discusses their structures, biological roles, representative inhibitors, and therapeutic potential, offering insights into the development of JmjC-KDM inhibitors.
DRUG DISCOVERY TODAY
(2023)
Article
Oncology
Heng Liu, Jianhuang Lin, Wei Zhou, Renyta Moses, Zhongping Dai, Andrew V. Kossenkov, Ronny Drapkin, Benjamin G. Bitler, Sergey Karakashev, Rugang Zhang
Summary: This study demonstrates that the extent of effector CD8+ T cell infiltration into tumors is influenced by a histone H3 demethylase (KDM5A) in epithelial ovarian cancer. KDM5A inhibits immune cell infiltration and antitumor immune responses by silencing genes involved in antigen processing and presentation. Inhibition of KDM5A restores gene expression in the antigen-presentation pathway and promotes antitumor immune responses mediated by CD8+ T cells.
CANCER IMMUNOLOGY RESEARCH
(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)
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
Cell Biology
Fangfang Dong, Min Chen, Min Chen, Lin Jiang, Zhiming Shen, Longfei Ma, Chunsheng Han, Xudong Guo, Fei Gao
Summary: PRMT5 is abundantly expressed in spermatogonial stem cells and its deletion leads to loss of SSCs and male infertility. Deficiency of Prmt5 in SSCs results in abnormal proliferation, cell cycle arrest, and increased apoptosis, along with alterations in gene expression and histone modifications.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2021)
Review
Oncology
Jayden Sterling, Sharleen V. Menezes, Ramzi H. Abbassi, Lenka Munoz
Summary: Histone lysine demethylases (KDMs) are enzymes that remove methylation marks on lysines in nucleosomes' histone tails, regulating gene transcription and playing important roles in cancer development. KDMs can have activating or repressing effects on gene transcription, regulating the expression of oncogenes and tumor suppressors.
INTERNATIONAL JOURNAL OF CANCER
(2021)
Article
Clinical Neurology
Lea M. Stitzlein, Achintyan Gangadharan, Leslie M. Walsh, Deokhwa Nam, Alexsandra B. Espejo, Melissa M. Singh, Kareena H. Patel, Yue Lu, Xiaoping Su, Ravesanker Ezhilarasan, Joy Gumin, Sanjay Singh, Erik Sulman, Frederick F. Lang, Joya Chandra
Summary: In this study, the efficacy of LSD1 inhibitors in patient-derived glioblastoma stem cell (GSC) models was evaluated. The results showed that LSD1 inhibitors had selective cytotoxic effects, but tumor regrowth occurred. Genes that may predict resistance to LSD1 inhibitors were identified using RNA-seq, providing guidance for future combination therapies.
FRONTIERS IN NEUROLOGY
(2023)
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
Integrative & Complementary Medicine
Li Zhong-Rui, Gu Meng-Zhen, Xu Xiao, Zhang Jing-Han, Zhang Hai-Li, Han Chao
Summary: This review highlights recent advances in natural LSD1 inhibitors, including their discovery and identification process, natural sources, chemical structures, anticancer effects, and structure-activity relationships. Natural products play an important role in drug discovery, particularly in cancer therapy.
CHINESE JOURNAL OF NATURAL MEDICINES
(2022)
Article
Hematology
Siyuan Xu, Siqing Wang, Shenghui Xing, Dingdang Yu, Bowen Rong, Hai Gao, Mengyao Sheng, Yun Tan, Xiaojian Sun, Kankan Wang, Kai Xue, Zhennan Shi, Fei Lan
Summary: Epigenetic abnormalities play a critical role in cancer, specifically in diseases like AML where aberrant fusion proteins drive the disease. The loss of KDM5A leads to differentiation and growth retardation in APL NB4 cells, by suppressing the expression of key target genes. Inhibition of KDMSA could greatly enhance differentiation in NB4 cells, suggesting a potential therapeutic target in APL treatment.
Article
Oncology
Damian Kovalovsky, Jeong Heon Yoon, Matthew G. Cyr, Samantha Simon, Elisaveta Voynova, Christoph Rader, Adrian Wiestner, Julie Alejo, Stefania Pittaluga, Ronald E. Gress
Summary: A novel CAR-T cell therapy targeting Siglec-6 for chronic lymphocytic leukemia was developed and shown to specifically target CLL cells. Additionally, Siglec-6 was identified as a potential target for immunotherapy based on the findings of this study.
Article
Cell Biology
Camille M. Lake, Kelsey Voss, Bradly M. Bauman, Katherine Pohida, Timothy Jiang, Gabriela Dveksler, Andrew L. Snow
Summary: The study demonstrated that TIM-3 plays a role in regulating RICD in both newly activated and late-stage effector T cells, with different effects at different stages. CEACAM1 also showed significant impact on RICD sensitivity, especially in protecting newly activated cells. These findings suggest that co-signaling proteins like TIM-3 and CEACAM1 can have implications for altering immune responses in effector T cells.
CELL DEATH & DISEASE
(2021)
Article
Biochemistry & Molecular Biology
Ashley E. Owens, Michael J. Iannotti, Tino W. Sanchez, Ty Voss, Abhijeet Kapoor, Matthew D. Hall, Juan J. Marugan, Sam Michael, Noel Southall, Mark J. Henderson
Summary: Cellular thermal shift assay (CETSA) is a valuable method for confirming target engagement in cellular environment. Traditional CETSA method measures changes in protein thermal stability using immunoblotting, which is low throughput and laborious. This study developed a high-throughput CETSA method that is compatible with 96- and 384-well microplates and removes thermally destabilized proteins using low speed centrifugation. It has been demonstrated to guide structure-activity relationship studies and compound screening.
ACS CHEMICAL BIOLOGY
(2022)
Article
Chemistry, Medicinal
Hongmao Sun, Nathan P. Coussens, Carina Danchik, Leah M. Wachsmuth, Mark J. Henderson, Samarjit Patnaik, Matthew D. Hall, Ashley L. Molinaro, Dayle A. Daines, Min Shen
Summary: This study identified potential inhibitors of NTHi VapC1 ribonuclease through virtual screening and scaffold hopping. These inhibitors could serve as starting points for preclinical development.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2022)
Article
Biochemistry & Molecular Biology
Yongwang Zhong, Wenjing Yan, Jingjing Ruan, Mike Fang, Changjun Yu, Shaojun Du, Ganesha Rai, Dingyin Tao, Mark J. Henderson, Shengyun Fang
Summary: XBP1 variant 1 (Xv1) is highly expressed in various types of cancer but not in normal tissues. It promotes cancer cell mitosis by upregulating TTLL6 expression, which is essential for spindle formation. This study reveals a new mechanism for Xv1-mediated cancer cell survival.
HUMAN MOLECULAR GENETICS
(2022)
Article
Biochemistry & Molecular Biology
Daniel R. Scoles, Mandi Gandelman, Sharan Paul, Thomas Dexheimer, Warunee Dansithong, Karla P. Figueroa, Lance T. Pflieger, Scott Redlin, Stephen C. Kales, Hongmao Sun, David Maloney, Robert Damoiseaux, Mark J. Henderson, Anton Simeonov, Ajit Jadhav, Stefan M. Pulst
Summary: CAG repeat expansions in the ATXN2 gene are associated with SCA2 and ALS. Lowering ATXN2 transcription can potentially treat these diseases.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Kevin J. Frankowski, Samarjit Patnaik, Chen Wang, Noel Southall, Dipannita Dutta, Soumitta De, Dandan Li, Christopher Dextras, Yi-Han Lin, Marthe Bryant-Connah, Danielle Davis, Feijun Wang, Leah M. Wachsmuth, Pranav Shah, Jordan Williams, Md Kabir, Edward Zhu, Bolormaa Baljinnyam, Amy Wang, Xin Xu, John Norton, Marc Ferrer, Steve Titus, Anton Simeonov, Wei Zheng, Lesley A. Mathews Griner, Ajit Jadhav, Jeffrey Aube, Mark J. Henderson, Udo Rudloff, Frank J. Schoenen, Sui Huang, Juan J. Marugan
Summary: The perinucleolar compartment (PNC) is a subnuclear body enriched with RNA transcripts and RNA-binding proteins. PNC prevalence is positively correlated with cancer progression and metastatic capacity. A high-throughput assay was developed to identify small molecules that can reduce PNC prevalence in cancer cells. The discovery of the pyrrolopyrimidine series led to the identification of the bioavailable analogue metarrestin, which has potent antimetastatic activity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Pharmacology & Pharmacy
Md Kabir, Elias C. Padilha, Pranav Shah, Ruili Huang, Srilatha Sakamuru, Eric Gonzalez, Lin Ye, Xin Hu, Mark J. Henderson, Menghang Xia, Xin Xu
Summary: CYP3A7 is an important xenobiotic metabolizing enzyme in the liver of human embryos, fetuses, and newborns. We identified chemical features important for CYP3A7 selectivity and established a dataset for future drug metabolism and interaction studies.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tino W. Sanchez, Michael H. Ronzetti, Ashley E. Owens, Maria Antony, Ty Voss, Eric Wallgren, Daniel Talley, Krishna Balakrishnan, Sebastian E. Leyes Porello, Ganesha Rai, Juan J. Marugan, Samuel G. Michael, Bolormaa Baljinnyam, Noel Southall, Anton Simeonov, Mark J. Henderson
Summary: Determining the mechanism of action for a molecule is crucial in chemical probe development and drug discovery. The cellular thermal shift assay (CETSA) is an effective tool to confirm target engagement in cells. A real-time CETSA (RT-CETSA) platform was developed to overcome the limitations of traditional CETSA experiments and enhance the sensitivity of target binding detection. This technology facilitates the assessment of the mechanism of action of small molecules.
ACS CHEMICAL BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Daniel A. Ciulla, Patricia Dranchak, John L. Pezzullo, Rebecca A. Mancusi, Alexandra Maria Psaras, Ganesha Rai, Jose-Luis Giner, James Inglese, Brian P. Callahan
Summary: This study developed a cellular reporter tool for noninvasive monitoring of human SHhC autoprocessing in high-throughput compatible plates, using cholesterol and bioluminescent nanoluciferase as readouts. The researchers developed WT and conditional mutant SHhC reporter lines to evaluate potential autoprocessing inhibitors and activators, respectively. They also designed a novel phosphonylated coelenterazine substrate for detecting nanoluciferase in the cell culture media. This new reporter system is valuable for small molecule discovery in cancer and developmental disorders where SHh ligand biosynthesis is dysregulated.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Quinlin M. Hanson, Nate Hoxie, Min Shen, Hui Guo, Ig-Jun Cho, Ipsita Chakraborty, Brooklyn M. Aragon, Ganesha Rai, Samarjit Patnaik, John S. Janiszewski, Matthew D. Hall
Summary: Target class profiling (TCP) is a chemistry biology approach used to investigate understudied biological targets. By developing a generalizable assay platform and screening curated compound libraries, TCP explores the chemical biological space of enzyme families. In this study, TCP was used to investigate inhibitory activity in a set of small-molecule methyltransferases (SMMTases) in order to explore this relatively unexplored target class. High-throughput screening (HTS)-amenable assays were optimized to screen a large number of small molecules against representative SMMTases, resulting in the identification of a novel inhibitor for the SMMTase HNMT.
ACS CHEMICAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Quinlin M. Hanson, Nate Hoxie, Min Shen, Hui Guo, Ig-Jun Cho, Ipsita Chakraborty, Brooklyn M. Aragon, Ganesha Rai, Samarjit Patnaik, John S. Janiszewski, Matthew D. Hall
Summary: Target class profiling (TCP) is a chemical biology approach to investigate understudied biological target classes. In this study, TCP was used to investigate inhibitory activity of small-molecule methyltransferases (SMMTases), and a novel inhibitor was discovered for the SMMTase HNMT.
ACS CHEMICAL BIOLOGY
(2023)
Article
Chemistry, Medicinal
Guangping Dong, Youchao Deng, Adam Yasgar, Ravi Yadav, Daniel Talley, Alexey Zakharov, Sankalp Jain, Ganesha Rai, Nicholas Noinaj, Anton Simeonov, Rong Huang
Summary: Venglustat has been identified as a potent inhibitor of NTMT1 with competitive binding at the peptide substrate site. This study reveals the importance of quinuclidine and fluorophenyl parts of Venglustat for NTMT1 inhibition. The research sheds light on NTMT1's biological roles and provides insights for future clinical investigations.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Joshua E. Hochuli, Sankalp Jain, Cleber Melo-Filho, Zoe L. Sessions, Tesia Bobrowski, Jun Choe, Johnny Zheng, Richard Eastman, Daniel C. Talley, Ganesha Rai, Anton Simeonov, Alexander Tropsha, Eugene N. Muratov, Bolormaa Baljinnyam, Alexey Zakharov
Summary: This study investigates whether compounds that bind the human angiotensin-converting enzyme 2 (ACE2) protein can reduce SARS-CoV-2 replication without affecting ACE2's enzymatic function. Through screening and in silico techniques, 73 ACE2 binders were identified, and five of them were found to inhibit the viral life cycle in human cells. These compounds serve as valuable starting points for the development of acute treatments for COVID-19 and research into host-directed therapy.
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
(2022)
Article
Biology
Katherine Pohida, Camille M. Lake, Debra Yee, Andrew L. Snow
Summary: This protocol describes the in vitro activation, expansion, and restimulation of primary T cells isolated from human donor peripheral blood, as well as methods to measure RICD sensitivity using flow cytometry.
