Review
Chemistry, Medicinal
Ranju Bansal, Anjleena Malhotra
Summary: Cancer is a serious health issue with available chemotherapeutic drugs being highly toxic and lacking selectivity. Advances in science have illuminated molecular pathways responsible for cancer, leading to the development of targeted anticancer agents, such as quinazoline derivatives. These agents act by inhibiting various protein kinases and other molecular targets, offering new opportunities for more effective cancer treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Organic
Jaideep B. Bharate, Jorgen Aden, Anna Gharibyan, Dan E. Adolfsson, Sanduni Wasana Jayaweera, Pardeep Singh, Katarina Vielfort, Mohit Tyagi, Mari Bonde, Sven Bergstrom, Anders Olofsson, Fredrik Almqvist
Summary: Diversely functionalized pyrimidine fused thiazolino-2-pyridones were synthesized via K2S2O8-mediated oxidative coupling, showing potential for inhibiting Alzheimer's disease-related fibril formation.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Nishant V. Sewgobind, Sanne Albers, Roland J. Pieters
Summary: Galectin-7 is a soluble lectin that binds specifically to beta-galactosides, involved in various biological processes such as apoptosis, proliferation, differentiation, adhesion, and migration. Understanding its physiological roles and potential as a drug target is crucial for developing inhibitors.
Article
Chemistry, Medicinal
Qiangsheng Zhang, Bo Chang, Qiang Feng, Lu Li
Summary: This study designed a series of novel G9a/GLP covalent inhibitors and discovered that compound ZZM-1220 exhibited strong anti-proliferative activity against triple-negative breast cancer. The drug could covalently bind to G9a/GLP and inhibit the production of H3K9me2, induce tumor cell apoptosis, and block the cell cycle progression. Moreover, ZZM-1220 demonstrated persistent inhibitory effects. Thus, ZZM-1220 holds promise as a lead compound for the development of G9a/GLP covalent inhibitors for the treatment of triple-negative breast cancer.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Momar Toure, Theresa Johnson, Bin Li, Ralf Schmidt, Hong Ma, Constantin Neagu, Andrea Unzue Lopez, Yanping Wang, Satenig Guler, YuFang Xiao, Renate Henkes, Kevin Ho, Susan Zhang, Chia Lin Chu, Uma Mahesh Gundra, Filippos Porichis, Long Li, Christine Katharina Maurer, Zhizhou Fang, Djordje Musil, Maria DiPoto, Emily Friis, Reinaldo Jones, Christopher Jones, James Cummings, Eugene Chekler, Eva Maria Tanzer, Bayard Huck, Brian Sherer
Summary: Hematopoietic progenitor kinase 1 (HPK1) is a validated target in pre-clinical immune oncology due to its regulation of critical signaling pathways in immune cells. Inhibiting HPK1 enhances T cell sensitivity to activation and anti-tumor activity in mice, suggesting its potential for enhancing anti-tumor immune response. Through structure-based drug design, potent HPK1 inhibitors were discovered with nanomolar potency in biomarkers and sustained elevation of IL-2 cytokine secretion.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Mohammed Abdalla Hussein, Rita M. Borik, Mohamed S. Nafie, Heba M. Abo-Salem, Sylvia A. Boshra, Zahraa N. Mohamed
Summary: This study successfully synthesized several novel anti-inflammatory quinazoline compounds by introducing sulfamerazine moieties, which showed good inhibitory activity against 3CLpro, cPLA2, and sPLA2. The synthesized compounds exhibited better inhibitory activity against SARS-CoV-2 main protease, sPLA2, and cPLA2 compared to baicalein and ivermectin.
Article
Chemistry, Medicinal
Kwang-Su Park, Yan Xiong, Hyerin Yim, Julia Velez, Nicolas Babault, Prashasti Kumar, Jing Liu, Jian Jin
Summary: Researchers have discovered the first covalent irreversible inhibitors of G9a/GLP, which can be used to study the functional roles of G9a and GLP by covalently modifying and inhibiting these methyltransferases.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Evangelos Bisyris, Eleni Zingkou, Golfo G. Kordopati, Minos Matsoukas, Plato A. Magriotis, Georgios Pampalakis, Georgia Sotiropoulou
Summary: A new in silico approach was used to design a kallikrein 7 (KLK7)-specific phosphonate activity-based probe (ABP) for quantifying active KLK7. The epidermal application of the ABP-inhibitor on Netherton syndrome model mice reversed disease hallmarks, showcasing the potential of using ABPs as theranostics.
CHEMICAL COMMUNICATIONS
(2021)
Article
Biochemistry & Molecular Biology
Hao Yang, Fang-Ting Wang, Min Wu, Wenjie Wang, Keli Agama, Yves Pommier, Lin -Kun An
Summary: In this study, 11-aminoalkoxy substituted benzophenanthridine derivatives were synthesized as selective TDP1 inhibitors. Six compounds showed high TDP1 inhibition potency, and the most potent inhibitor 14 induced cellular TDP1cc formation and exhibited synergistic effect with topotecan in various cancer cell lines.
BIOORGANIC CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Martin Golkowski, Andrea Lius, Tanmay Sapre, Ho-Tak Lau, Taylor Moreno, Dustin J. Maly, Shao-En Ong
Summary: Dynamic changes in protein-protein interaction networks have significant implications for cellular functions and human diseases. Our study presents a quantitative mass spectrometry-based chemoproteomic method called kinobead competition and correlation analysis (kiCCA) that enables rapid and extensive profiling of kinase interactomes. Using kiCCA, we identified context-dependent kinase interactome changes in diverse cancer lines and discovered potential drug targets. Our findings highlight the importance of studying kinase interactome dynamics for understanding cellular signaling in health and disease.
Article
Biochemistry & Molecular Biology
Shruti Choudhary, Arpit Doshi, Lerin Luckett-Chastain, Michael Ihnat, Ernest Hamel, Susan L. Mooberry, Aleem Gangjee
Summary: The efficacy of quinazoline-based antiglioma agents is attributed to their effects on microtubule dynamics and inhibition of multiple intracellular targets. Quinazolines not only cause microtubule depolymerization, but also act as low nanomolar inhibitors of EGFR, VEGFR-2, and PDGFR-α. This multitarget activity demonstrates their potential antitumor effects by targeting multiple pathways.
BIOORGANIC & MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Dongyan Gu, Mengmeng Zhang, Lvtao Cai, Chang Wang, Yu -Bo Zhou, Jia Li, Rong Sheng
Summary: Compound 1 with pyrazolo[1,5-a]quinoxalin-4(5H)-one scaffold was identified as a hit for inhibiting PI3K alpha activity through virtual screening. Structural modifications based on similarity search and molecular docking yielded a novel series of pyrazolo[1,5-a]quinoxalin-4(5H)-one derivatives. The most potent compound 49b exhibited improved PI3K alpha inhibitory activity with good isoform selectivity and demonstrated promising pharmacokinetic properties. Further development of compound 49b as a potential PI3Ka inhibitor is warranted.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
Qizhi Geng, Yue-Yu Kong, Weizhe Li, Jianhao Zhang, Haoli Ma, Yuhang Zhang, Lin-Tai Da, Yan Zhao, Hai-Ning Du
Summary: This study uncovers that, during mitosis, the kinase Plk1 and the phosphatase PPP2CB dynamically phosphorylates/dephosphorylates the methyltransferase G9a to regulate H3K9me2 levels, chromatin accessibility, and mitotic progression, which highlights the importance of the crosstalk in chromatin organization and mitotic events.
Article
Food Science & Technology
Jia Ying Wang, Youjin Baek, Eun Woo Jeong, Hyeon Gyu Lee
Summary: This study focuses on optimizing the preparation conditions of CoQ10-loaded liposomes to overcome the limitations of conventional liposomes. The study evaluates the concentrations of cholesterol and beta-sitosterol, as well as CoQ10, and their effects on particle size and entrapment efficiency. The study also investigates how these components impact the stability, adhesion property, and antioxidant activity of the liposomes. The findings suggest that beta-sitosterol has the potential to enhance the physicochemical attributes of CoQ10-loaded liposomes, proposing applications in the food and pharmaceutical industries.
Article
Chemistry, Medicinal
Zongbo Feng, Chunju Yang, Yi Zhang, Huaxuan Li, Wei Fang, Junhua Wang, Yichu Nie, Chang-Yun Wang, Zhiqing Liu, Zhimin Jiang, Junjian Wang, Yuanxiang Wang
Summary: Protein lysine methyltransferases G9a and GLP are important in cellular processes. A covalent inhibitor, compound 27, has been discovered to effectively inhibit cell proliferation and reduce H3K9me2 levels. It also shows significant antitumor efficacy in vivo.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Magdalena M. Szewczyk, Yoshinori Ishikawa, Shawna Organ, Nozomu Sakai, Fengling Li, Levon Halabelian, Suzanne Ackloo, Amber L. Couzens, Mohammad Eram, David Dilworth, Hideto Fukushi, Rachel Harding, Carlo C. dela Sena, Tsukasa Sugo, Kozo Hayashi, David McLeod, Carlos Zepeda, Ahmed Aman, Maria Sanchez-Osuna, Eric Bonneil, Shinji Takagi, Rima Al-Awar, Mike Tyers, Stephane Richard, Masayuki Takizawa, Anne-Claude Gingras, Cheryl H. Arrowsmith, Masoud Vedadi, Peter J. Brown, Hiroshi Nara, Dalia Barsyte-Lovejoy
NATURE COMMUNICATIONS
(2020)
Article
Biochemistry & Molecular Biology
Gustavo A. Bezerra, Alexander Holenstein, William R. Foster, Bing Xie, Kevin G. Hicks, Celine Buerer, Seraina Lutz, Ayan Mukherjee, Dipika Sarkar, Debomita Bhattacharya, Jared Rutter, Arindam Talukdar, Peter J. Brown, Minkui Luo, Lei Shi, D. Sean Froese, Wyatt W. Yue
Summary: This study identified a novel compound, (S)-SKI-72, which can stabilize the regulatory domain of MTHFR and effectively inhibit the enzyme's activity. This finding provides a new candidate drug for the development of MTHFR inhibitors.
Article
Chemistry, Medicinal
Yudao Shen, Fengling Li, Magdalena M. Szewczyk, Levon Halabelian, Irene Chau, Mohammad S. Eram, Carlo Dela Sena, Kwang-Su Park, Fanye Meng, He Chen, Hong Zeng, Aiping Dong, Hong Wu, Viacheslav V. Trush, David McLeod, Carlos A. Zepeda-Velazquez, Robert M. Campbell, Mary M. Mader, Brian M. Watson, Matthieu Schapira, Cheryl H. Arrowsmith, Rima Al-Awar, Dalia Barsyte-Lovejoy, H. Umit Kaniskan, Peter J. Brown, Masoud Vedadi, Jian Jin
Summary: (R)-2 is a potent and highly selective inhibitor of PRMT6, binding to an induced allosteric pocket. It shows outstanding selectivity for PRMT6 over other methyltransferases and can be used as a valuable tool for further investigation of PRMT6 functions in health and disease.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Anja Doelle, Bikash Adhikari, Andreas Kraemer, Janik Weckesser, Nicola Berner, Lena-Marie Berger, Mathias Diebold, Magdalena M. Szewczyk, Dalia Barsyte-Lovejoy, Cheryl H. Arrowsmith, Jakob Gebel, Frank Loehr, Volker Doetsch, Martin Eilers, Stephanie Heinzlmeir, Bernhard Kuster, Christoph Sotriffer, Elmar Wolf, Stefan Knapp
Summary: H3K4 methylation is a hallmark of actively transcribed genes, with WDR5 associated with noncoding RNAs and MYC. WDR5 has been identified as a potential drug target, and the design of WDR5 degraders and the nature of the linker play a key role in degradation efficacy.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Review
Biotechnology & Applied Microbiology
Qin Wu, Matthieu Schapira, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy
Summary: PRMTs are emerging as attractive therapeutic targets due to their regulation of essential biological processes such as transcription, splicing, RNA biology, DNA damage response, and cell metabolism, which are often disrupted in diseases. Understanding how these enzymes support cancer cell growth in specific metabolic contexts or in the presence of certain mutations has provided the rationale for targeting them in oncology, with ongoing inhibitor development and in-depth mechanistic investigations guiding future clinical development.
NATURE REVIEWS DRUG DISCOVERY
(2021)
Article
Oncology
Steven P. Angus, Timothy J. Stuhlmiller, Gaurav Mehta, Samantha M. Bevill, Daniel R. Goulet, J. Felix Olivares-Quintero, Michael P. East, Maki Tanioka, Jon S. Zawistowski, Darshan Singh, Noah Sciaky, Xin Chen, Xiaping He, Naim U. Rashid, Lynn Chollet-Hinton, Cheng Fan, Matthew G. Soloway, Patricia A. Spears, Stuart Jefferys, Joel S. Parker, Kristalyn K. Gallagher, Andres Forero-Torres, Ian E. Krop, Alastair M. Thompson, Rashmi Murthy, Michael L. Gatza, Charles M. Perou, H. Shelton Earp, Lisa A. Carey, Gary L. Johnson
Summary: Inhibition of the pioneer transcription factor FOXA1 may disrupt adaptive responses of HER2+ breast cancer cells to drugs and enhance the efficacy of anti-HER2 therapy. Research has shown that HER2+ cells with higher responsiveness exhibit transcriptional and epigenetic changes related to FOXA1 when inhibited by lapatinib.
Review
Cell Biology
Xin Chen, Joshua Drew, Wren Berney, Wei Lei
Summary: Natural products have attracted interest in the research community and pharmaceutical industry for their neuroprotective activity against Alzheimer's disease (AD). They target different pathological mechanisms associated with AD and their mixtures or extracts containing multiple bioactive compounds may exhibit multiple neuroprotective mechanisms, offering a potential approach for AD drug discovery.
Article
Chemistry, Physical
Xiangda Peng, Michael Baxa, Nabil Faruk, Joseph R. Sachleben, Sebastian Pintscher, Isabelle A. Gagnon, Scott Houliston, Cheryl H. Arrowsmith, Karl F. Freed, Gabriel J. Rocklin, Tobin R. Sosnick
Summary: Combining denaturant dependence of hydrogen-deuterium exchange (HDX) and molecular dynamics (MD) allows for accurate identification of individual hydrogen bonds breaking and mapping the free energy surface (FES) of proteins. The new and extremely fast MD package Upside has been shown to accurately model protein folding compared to all-atom methods. By modifying the energy function using machine-learning, Upside's accuracy has significantly improved in replicating HDX data and protein stability. However, challenges remain in accurately calculating FESs in simulations.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2022)
Article
Chemistry, Medicinal
Mandeep K. Mann, Carlos A. Zepeda-Velazquez, Hector Gonzalez-Alvarez, Aiping Dong, Taira Kiyota, Ahmed M. Aman, Peter Loppnau, Yanjun Li, Brian Wilson, Cheryl H. Arrowsmith, Rima Al-Awar, Rachel J. Harding, Matthieu Schapira
Summary: A chemical probe targeting USP5 has been developed and shown to competitively inhibit the enzyme's catalytic activity by occupying the C-terminal ubiquitin-binding site. Compound 64 has high binding affinity to USP5 and selectivity over other proteins, providing a potential tool for elucidating the function of USP5 in cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Correction
Chemistry, Medicinal
Mandeep K. Mann, Carlos A. Zepeda-Velazquez, Hector Gonzalez-Alvarez, Aiping Dong, Taira Kiyota, Ahmed M. Aman, Peter Loppnau, Yanjun Li, Brian Wilson, Cheryl H. Arrowsmith, Rima Al-Awar, Rachel J. Harding, Matthieu Schapira
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Kate M. MacDonald, Shirony Nicholson-Puthenveedu, Maha M. Tageldein, Sarika Khasnis, Cheryl H. Arrowsmith, Shane M. Harding
Summary: This study identifies features of micronuclei chromatin that determine cGAS recruitment to micronuclei and activation of associated pathways.
NATURE COMMUNICATIONS
(2023)
Article
Cell Biology
Navdeep Malik, Hualong Yan, Young-Im Kim, Gamze Ayaz, Shasha Wang, Payel Mondal, Ji Luo, Jing Huang
Summary: Autophagy plays a crucial role in tumor initiation and progression, but targeting it in cancer treatment is challenging due to genetic or epigenetic factors. However, dysregulation of mitochondrial translation caused by CBFB deficiency can sensitize tumors to autophagy inhibition. CBFB deficiency leads to elevated autophagy and mitophagy in estrogen receptor-positive breast tumors, making them hypersensitive to autophagy inhibition. Inhibiting autophagy selectively eliminates breast tumor cells with mitochondrial translation defects resulting from CBFB deficiency.
Article
Chemistry, Medicinal
Serah W. Kimani, Julie Owen, Stuart R. Green, Fengling Li, Yanjun Li, Aiping Dong, Peter J. Brown, Suzanne Ackloo, David Kuter, Cindy Yang, Miranda MacAskill, Stephen Scott MacKinnon, Cheryl H. Arrowsmith, Matthieu Schapira, Vijay Shahani, Levon Halabelian
Summary: DCAF1 serves as a subunit for RING-type CRL4(DCAF1) and HECT family EDVPDCAF1 E3 ubiquitin ligases in substrate recruitment. The WDR domain of DCAF1 acts as a binding platform for substrate proteins and is targeted by HIV and SIV lentiviral adaptors. This study used a proteome-scale drug-target interaction prediction model to identify ligands for the DCAF1 WDR domain through biophysical screening and X-ray crystallography, confirming the selective binding of a predicted ligand. The findings demonstrate the successful application of artificial intelligence-enabled virtual screening methods in the absence of previously known ligands.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2023)
Article
Biology
Serah W. Kimani, Sumera Perveen, Magdalena Szewezyk, Hong Zeng, Aiping Dong, Fengling Li, Pegah Ghiabi, Yanjun Li, Irene Chau, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy, Vijayaratnam Santhakumar, Masoud Vedadi, Levon Halabelian
Summary: Cbl-b, a RING-type E3 ubiquitin ligase, negatively regulates immune cell activity and is considered an attractive target for cancer immunotherapy. A novel Cbl-b inhibitor, C7683, binds strongly to Cbl-b and inhibits its activity by locking the protein in an inactive conformation. This study provides structural insights into the inhibition mechanism of Cbl-b.
COMMUNICATIONS BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Samir H. Barghout, Mandeep K. Mann, Ahmed Aman, Yifan Yu, Matthew G. Alteen, Aaron D. Schimmer, Matthieu Schapira, Cheryl H. Arrowsmith, Dalia Barsyte-Lovejoy
Summary: This study identifies epigenetic regulators that can significantly enhance the cytotoxicity of the anticancer drug TAK-243. These regulators exert their effects by inhibiting the efflux transporter ABCG2. The study also develops a cell-based assay to quantitatively evaluate the ABCG2-inhibitory activity of drug candidates.
ACS CHEMICAL BIOLOGY
(2022)
