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
Chemistry, Medicinal
Carlo Baggio, Anna Kulinich, Cassandra N. Dennys, Rochelle Rodrigo, Kathrin Meyer, Iryna Ethell, Maurizio Pellecchia
Summary: The study utilized an innovative NMR-guided screening and ligand design approach to derive low-molecular-weight ligands capable of mimicking interactions elicited by ephrin ligands. These agents demonstrated nanomolar affinity, activated receptors in cellular assays with motor neurons, and provided significant motor neuron protection from ALS patient-derived astrocytes. Structural studies on the complex between the ligand-binding domain and the most active agent offered insights into the agents' mechanism at a molecular level, forming a strong foundation for potential treatment of ALS and other human diseases.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Dandan Liu, Huan Ge, Fangling Xu, Yufang Xu, Wenjun Liu, Honglin Li, Lili Zhu, Yanyan Diao, Zhenjiang Zhao
Summary: A class of 2-aminopyridine derivatives as potent and selective JAK2 inhibitors was obtained through drug design and synthesis. Compound 21b showed high inhibitory activity and selectivity against JAK2, indicating its potential as a therapeutic agent for myeloproliferative neoplasms.
CHINESE CHEMICAL LETTERS
(2022)
Article
Chemistry, Medicinal
Dalton R. Kim, Meghan J. Orr, Ada J. Kwong, Kristine K. Deibler, Hasan H. Munshi, Cory Seth Bridges, Taylor Jie Chen, Xiaoyu Zhang, H. Daniel Lacorazza, Karl A. Scheidt
Summary: The mitogen-activated protein kinase (MAPK) signaling cascade is essential for regulating various cellular activities across eukaryotes. In this study, a novel class of irreversible MAP2K7 inhibitors was designed and synthesized, with promising in vitro potency and selectivity, as well as favorable cellular activity. These compounds show potential as powerful tools for studying pediatric T cell acute lymphoblastic leukemia (T-ALL).
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Chemistry, Medicinal
Chamandi S. Dampalla, Athri D. Rathnayake, Anushka C. Galasiti Kankanamalage, Yunjeong Kim, Krishani Dinali Perera, Harry Nhat Nguyen, Matthew J. Miller, Trent K. Madden, Hunter R. Picard, Hayden A. Thurman, Maithri M. Kashipathy, Lijun Liu, Kevin P. Battaile, Scott Lovell, Kyeong-Ok Chang, William C. Groutas
Summary: The 3C-like protease (3CLpro) of SARS-CoV-2 has been validated as an effective target for developing therapeutics. Highly potent inhibitors have been successfully designed based on structure-guided design, and their mechanism of action has been established using high-resolution cocrystal structures.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Multidisciplinary
Daiki Yamane, Satsuki Onitsuka, Suyong Re, Hikaru Isogai, Rui Hamada, Tadanari Hiramoto, Eiji Kawanishi, Kenji Mizuguchi, Naoya Shindo, Akio Ojida
Summary: This study reports an irreversible inhibitor of SARS-CoV-2 M-pro with chlorofluoroacetamide (CFA) as a covalent modification agent. The (R,R)-18 isomer showed higher inhibitory activity against M-pro than other isomers. The findings highlight the influence of CFA chirality on the covalent modification of proteinous cysteines and provide a basis for improving the potency and selectivity of CFA-based covalent inhibitors.
Article
Biochemistry & Molecular Biology
Min Wang, Li Lan, Yu-Wei Wang, Jin-Yang Zhang, Lei Shi, Li-Ping Sun
Summary: Aberrant FGF19/FGFR4 signaling is a driver of growth and survival in hepatocellular carcinoma. Selective FGFR4 inhibitors are being researched as potential drugs for targeted therapy, but none have been approved by the FDA. In this study, a series of arylurea derivatives were designed and synthesized as novel irreversible covalent FGFR4 inhibitors. Compound 6v demonstrated significant inhibition of FGFR4 phosphorylation and downstream signaling in Hep3B cells, indicating its potential for further research and optimization.
BIOORGANIC & MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Rachel A. Rowlands, Qiuyan Chen, Renee A. Bouley, Larisa Avramova, John J. G. Tesmer, Andrew D. White
Summary: The ability of GRK2 and GRK5 to regulate GPCR desensitization makes them attractive targets for heart failure and cancer treatment. Previous research showed potential for selective inhibition of GRK5 over GRK2 using a specific residue, but the inhibitors were not very potent. A new study successfully adapted an indolinone scaffold with covalent warheads, creating compounds with high selectivity for GRK5 and low nanomolar potency.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Matthew P. Davies, Rocio Benitez, Concepcion Perez, Sven Jakupovic, Philip Welsby, Klaudia Rzepecka, Jane Alder, Colin Davidson, Ana Martinez, Joseph M. Hayes
Summary: The study introduces the in silico design, screening, and in vitro validation of potent GSK-3 beta type-II inhibitors, leading to the identification of highly potent nanomolar inhibitors with potential neuroprotective effects. The designed inhibitors show promise as a potential route toward more clinically effective GSK-3 beta inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Bingchen Yu, Shanshan Li, Takako Tabata, Nanxi Wang, Li Cao, G. Renuka Kumar, Wei Sun, Jun Liu, Melanie Ott, Lei Wang
Summary: This study developed covalent nanobodies that bind irreversibly with SARS-CoV-2, increasing neutralization potency against wild-type virus and its variants. These insights into increased potency can be valuable for developing effective therapeutics against viral infections.
Article
Chemistry, Medicinal
Isabella Romeo, Antonella Brizzi, Federica Pessina, Francesca Alessandra Ambrosio, Francesca Aiello, Carmela Belardo, Gabriele Carullo, Giosue Costa, Luciano De Petrocellis, Maria Frosini, Livio Luongo, Samuele Maramai, Marco Paolino, Aniello Schiano Moriello, Claudia Mugnaini, Francesco Scorzelli, Sabatino Maione, Federico Corelli, Vincenzo Di Marzo, Stefano Alcaro, Anna Artese
Summary: We developed a rational drug design strategy and synthesized ligands to improve the binding properties and potency of a previously identified TRPV1 agonist. Molecular modeling and simulations guided the design towards introducing a lipophilic iodine and a flat pyridine/benzene at a specific position in the ligand. Most synthesized compounds showed high TRPV1 efficacy, selectivity, and protective properties against oxidative stress-induced ROS formation. The compounds also exhibited neuroprotective and antinociceptive effects in biological evaluations.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Brian C. Sanders, Suman Pokhrel, Audrey D. Labbe, Irimpan I. Mathews, Connor J. Cooper, Russell B. Davidson, Gwyndalyn Phillips, Kevin L. Weiss, Qiu Zhang, Hugh O'Neill, Manat Kaur, Jurgen G. Schmidt, Walter Reichard, Surekha Surendranathan, Jyothi Parvathareddy, Lexi Phillips, Christopher Rainville, David E. Sterner, Desigan Kumaran, Babak Andi, Gyorgy Babnigg, Nigel W. Moriarty, Paul D. Adams, Andrzej Joachimiak, Brett L. Hurst, Suresh Kumar, Tauseef R. Butt, Colleen B. Jonsson, Lori Ferrins, Soichi Wakatsuki, Stephanie Galanie, Martha S. Head, Jerry M. Parks
Summary: Designed a series of protease inhibitors targeting SARS-CoV-2, with the most effective inhibitor capable of blocking viral replication in mammalian cells and showing no significant inhibition of human proteases. These findings present an opportunity for the development of protease inhibitors.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Mark E. Layton, Jeffrey C. Kern, Timothy J. Hartingh, William D. Shipe, Izzat Raheem, Monika Kandebo, Robert P. Hayes, Sarah Huszar, Donnie Eddins, Bennett Ma, Joy Fuerst, Gordon K. Wollenberg, Jing Li, Jeff Fritzen, Georgia B. McGaughey, Jason M. Uslaner, Sean M. Smith, Paul J. Coleman, Christopher D. Cox
Summary: PDE10A is an important regulator of striatal signaling. Inhibition of PDE10A may offer a new treatment option for schizophrenia. This study describes the discovery of an isomeric pyrimidine series that led to the development of compound 18 (MK-8189), which is currently in Phase 2b clinical development for schizophrenia.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ruifang Jia, Jian Zhang, Chiara Bertagnin, Srinivasulu Cherukupalli, Wei Ai, Xiao Ding, Zhuo Li, Jiwei Zhang, Han Ju, Xiuli Ma, Arianna Loregian, Bing Huang, Peng Zhan, Xinyong Liu
Summary: The structural modifications at the 150-cavity of influenza virus neuraminidases can result in more potent oseltamivir derivatives, with compound 5c showing the most promising activity. In vitro and in vivo studies demonstrated low cytotoxicity and no acute toxicity of 5c, indicating its potential as a drug candidate.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Dawid Panek, Anna Pasieka, Gniewomir Latacz, Paula Zareba, Michal Szczech, Justyna Godyn, Fabien Chantegreil, Florian Nachon, Xavier Brazzolotto, Anna Skrzypczak-Wiercioch, Maria Walczak, Magdalena Smolik, Kinga Salat, Georg Hoefner, Klaus Wanner, Anna Wieckowska, Barbara Malawska
Summary: A highly selective hBuChE inhibitor (29) with potential benefits for treating Alzheimer's disease has been identified through extensive in vitro and in vivo evaluations.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Multidisciplinary
James Rae, Kay Yeung, Joseph J. W. McDouall, David J. Procter
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2016)
Article
Chemistry, Medicinal
Jason G. Kettle, Peter Ballard, Catherine Bardelle, Mark Cockerill, Nicola Colclough, Susan E. Critchlow, Judit Debreczeni, Gary Fairley, Shaun Fillery, Mark A. Graham, Louise Goodwin, Sylvie Guichard, Kevin Hudson, Richard A. Ward, David Whittaker
JOURNAL OF MEDICINAL CHEMISTRY
(2015)
Article
Chemistry, Multidisciplinary
Kay Yeung, Rebecca E. Ruscoe, James Rae, Alexander P. Pulis, David J. Procter
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2016)
Article
Chemistry, Medicinal
Robert H. Bradbury, Rowena Callis, Gregory R. Carr, Huawei Chen, Edwin Clark, Lyman Feron, Steve Glossop, Mark A. Graham, Maureen Hattersley, Chris Jones, Scott G. Lamont, Gilles Ouvry, Anil Patel, Joe Patel, Alfred A. Rabow, Craig A. Roberts, Stephen Stokes, Natalie Stratton, Graeme E. Walker, Lara Ward, David Whalley, David Whittaker, Gail Wrigley, Michael J. Waring
JOURNAL OF MEDICINAL CHEMISTRY
(2016)
Article
Chemistry, Organic
Ryan Greenwood, Kay Yeung
TETRAHEDRON LETTERS
(2016)
Article
Chemistry, Medicinal
Richard A. Ward, Paul Bethel, Calum Cook, Emma Davies, Judit E. Debreczeni, Gary Fairley, Lyman Feron, Vikki Flemington, Mark A. Graham, Ryan Greenwood, Nicola Griffin, Lyndsey Hanson, Philip Hoperoft, Tina D. Howard, Julian Liudson, Michael James, Clifford D. Jones, Christopher R. Jones, Scott Lamont, Richard Lewis, Nicola Lindsay, Karen Roberts, Iain Simpson, Steve St-Gallay, Steve Swallow, Jia Tang, Michael Tonge, Zhenhua Wang, Baochang Zhai
JOURNAL OF MEDICINAL CHEMISTRY
(2017)
Article
Chemistry, Multidisciplinary
James R. Smith, Beatrice S. L. Collins, Matthew J. Hesse, Mark A. Graham, Eddie L. Myers, Varinder K. Aggarwal
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2017)
Review
Chemistry, Multidisciplinary
Alexander P. Pulis, Kay Yeung, David J. Procter
Article
Chemistry, Organic
Allan Dishington, J. Lyman Feron, Kathryn Gill, Mark A. Graham, Ian Hollingsworth, Jennifer H. Pink, Andrew Roberts, Iain Simpson, Matthew Tatton
Article
Chemistry, Physical
Kay Yeung, Fabien J. T. Talbot, Gareth P. Howell, Alexander P. Pulis, David J. Procter
Article
Chemistry, Medicinal
Richard A. Ward, Mark J. Anderton, Paul Bethel, Jason Breed, Calum Cook, Emma J. Davies, Andrew Dobson, Zhiqiang Dong, Gary Fairley, Paul Farrington, Lyman Feron, Vikki Flemington, Francis D. Gibbons, Mark A. Graham, Ryan Greenwood, Lyndsey Hanson, Philip Hopcroft, Rachel Howells, Julian Hudson, Michael James, Clifford D. Jones, Christopher R. Jones, Yongchao Li, Scott Lamont, Richard Lewis, Nicola Lindsay, James McCabe, Thomas McGuire, Philip Rawlins, Karen Roberts, Linda Sandin, Iain Simpson, Steve Swallow, Jia Tang, Gary Tomkinson, Michael Tonge, Zhenhua Wang, Baochang Zhai
JOURNAL OF MEDICINAL CHEMISTRY
(2019)
Article
Chemistry, Applied
Mark A. Graham, Hannah Askey, Andrew D. Campbell, Lai Chan, Katie G. Cooper, Zhaoshan Cui, Andrew Dalgleish, David Dave, Gareth Ensor, Maria Rita Galan Espinosa, Peter Hamilton, Claire Heffernan, Lucinda Jackson, Dajiang Jing, Martin F. Jones, Pengpeng Liu, Keith R. Mulholland, Mohammed Pervez, Michael Popadynec, Emma Randles, Simone Tomasi, Shenghua Wang
Summary: Ceralasertib, currently under evaluation in clinical trials for cancer treatment, has a complex structure that poses challenges for large-scale synthesis. Researchers have developed a new synthetic route that successfully produces high-quality ceralasertib with low impurities and a high overall yield.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)
Article
Chemistry, Applied
Mark A. Graham, Gary Noonan, Janette H. Cherryman, James J. Douglas, Miguel Gonzalez, Lucinda Jackson, Kevin Leslie, Zhi-qing Liu, David McKinney, Rachel H. Munday, Chris D. Parsons, David T. E. Whittaker, En-xuan Zhang, Jun-wang Zhang
Summary: New route development activities for ceralasertib have led to the discovery of an efficient, acid additive-free, photoredox Minisci reaction. Mechanistic understanding and optimization of the catalyst system has significantly enhanced the reaction rate, with a large-scale continuous photoflow process providing promising proof-of-concept data for future clinical manufacture applications of ceralasertib.
ORGANIC PROCESS RESEARCH & DEVELOPMENT
(2021)