Article
Multidisciplinary Sciences
Tadatoshi Sato, Christian D. Castro Andrade, Sung-Hee Yoon, Yingshe Zhao, William J. Greenlee, Patricia C. Weber, Usha Viswanathan, John Kulp, Daniel J. Brooks, Marie B. Demay, Mary L. Bouxsein, Bruce Mitlak, Beate Lanske, Marc N. Wein
Summary: This study identifies SIK2/SIK3 as potential drug targets for treating osteoporosis and successfully develops an orally available SIK2/SIK3 inhibitor. The inhibitor stimulates bone formation and increases bone density without apparent toxicity. These findings provide a new approach for the pharmacological treatment of osteoporosis.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
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, Medicinal
Horacio Perez-Sanchez, Helena den Haan, Alfonso Perez-Garrido, Jorge Pena-Garcia, Sandipan Chakraborty, Ilkay Erdogan Orhan, Fatma Sezer Senol Deniz, Jose Manuel Villalgordo
Summary: Acetylcholinesterase inhibitors are crucial in treating Alzheimer's disease, and a study identified several potential compounds through drug repurposing screening. Experimental evaluations showed three compounds with high AChE inhibition ability and selectivity, suggesting promising therapeutic potential.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Biochemistry & Molecular Biology
Reinad R. Abu Rabah, Anusha Sebastian, Srinivasulu Vunnam, Shaista Sultan, Hamadeh Tarazi, Hanan S. Anbar, Mahmoud K. Shehata, Seyed-Omar Zaraei, Sara M. Elgendy, Salma A. Al Shamma, Hany A. Omar, Taleb H. Al-Tel, Mohammed El-Gamal
Summary: The study reports on a new series of pyrazole derivatives with potential anticancer activity. Compound 1f showed the most potent anticancer activity against various cancer cell lines, even more potent than sorafenib and SP600125. Compounds 1b, 1c, and 1h demonstrated strong anti-proliferative activity against hepatocellular carcinoma cell lines. The study also discovered two potent JNK3 inhibitors, compounds 1c and 1f, with good inhibitory effects in whole-cell assays.
BIOORGANIC & MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Xue-Mei Zheng, Yuan-Si Chen, Yu-Juan Ban, Yu-Jie Wang, Yong-Xi Dong, Li Lei, Bing Guo, Jian-Ta Wang, Lei Tang, Hong-Liang Li, Ji-Quan Zhang
Summary: In this study, a series of substituted benzoxazole derivatives were designed and synthesized. The compound 18a showed higher inhibitory activity against PI3Kα and better anti-cancer effects, as well as improved selectivity and pharmacokinetic properties.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Oncology
Shenghui Feng, Fangyi Wei, Haoran Shi, Shen Chen, Bangqi Wang, Deqiang Huang, Lingyu Luo
Summary: This review provides a comprehensive summary of the roles of SIKs in different cancers. It reveals that SIK1 is generally considered a tumor suppressor protein, while SIK2 and SIK3 are often associated with tumor promotion. However, the functions of SIKs show contradictory results in certain cases. The article aims to elucidate the clinical significance of SIKs and discuss potential therapeutic strategies targeting SIKs in cancer treatment.
INTERNATIONAL JOURNAL OF ONCOLOGY
(2023)
Review
Pharmacology & Pharmacy
Yazan Haddad, Marek Remes, Vojtech Adam, Zbynek Heger
Summary: The study utilized variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. These families shared similar mutational profiles, ligand R-groups facing the C-helix, mutation sites, and DFG domain.
DRUG DISCOVERY TODAY
(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
Momen R. Fareed, Mai E. Shoman, Mohammed I. A. Hamed, Mohamed Badr, Hanin A. Bogari, Sameh S. Elhady, Tarek S. Ibrahim, Gamal El-Din A. Abuo-Rahma, Taha F. S. Ali
Summary: A series of 3-benzylideneindolin-2-one compounds were designed and synthesized based on the structures of combretastatin A-4 and compound IC261. These compounds showed significant growth inhibition against PC-3, MCF-7 and COLO-205 cells, with some exhibiting potent activity against COLO-205 with IC50 values of 0.2 and 0.3 mu M. Mechanistic studies demonstrated their efficacy in inhibiting microtubule assembly, CK1, and EGFR, inducing apoptosis and dysregulating apoptotic markers. These compounds are considered promising multitarget agents against colon cancer.
Article
Pharmacology & Pharmacy
Tatiana Antonio, Patricio Soares-da-Silva, Nuno M. Pires, Pedro Gomes
Summary: SIKs, as a member of the AMPK family, phosphorylate multiple targets to coordinate signaling pathways involved in metabolism, cell growth, apoptosis, and inflammation, playing a crucial role in PAH pathophysiology.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Peter 't Hart, Pascal Hommen, Anais Noisier, Adrian Krzyzanowski, Darijan Schueler, Arthur T. Porfetye, Mohammad Akbarzadeh, Ingrid R. Vetter, Helene Adihou, Herbert Waldmann
Summary: Researchers have developed peptide inhibitors targeting RbAp48 protein, successfully inhibiting the interaction between RbAp48 and MTA1 with high stability. Through a structure-based design strategy, the goal of improving affinity was achieved.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Biology
Cheng-Chia Tang, Christian D. Castro Andrade, Maureen J. O'Meara, Sung-Hee Yoon, Tadatoshi Sato, Daniel J. Brooks, Mary L. Bouxsein, Janaina da Silva Martins, Jinhua Wang, Nathanael S. Gray, Barbara Misof, Paul Roschger, Stephane Boulin, Klaus Klaushofer, Annegreet Velduis-Vlug, Yosta Vegting, Clifford J. Rosen, Daniel O'Connell, Thomas B. Sundberg, Ramnik J. Xavier, Peter Ung, Avner Schlessinger, Henry M. Kronenberg, Rebecca Berdeaux, Marc Foretz, Marc N. Wein
Summary: The study found that the multi-kinase inhibitor YKL-05-099 may be a promising new class of bone anabolic agents that increase bone formation without increasing bone resorption, potentially overcoming limitations of current osteoporosis therapies.
Article
Chemistry, Medicinal
Michael Bauder, Christian Meyners, Patrick L. Purder, Stephanie Merz, Wisely Oki Sugiarto, Andreas M. Voll, Tim Heymann, Felix Hausch
Summary: The design and synthesis of macrocyclic FKBP51-selective ligands with high affinity and selectivity through incorporation of polar functionalities demonstrates a viable strategy to target the shallow FKBP51 binding site selectively. The high-resolution crystal structures of six macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode, highlighting the potential of macrocyclization as an effective approach in drug development.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Multidisciplinary Sciences
Magdalena Vavakova, Kaisa Hofwimmer, Jurga Laurencikiene, Olga Goransson
Summary: Salt-inducible kinase 2 (SIK2) is highly expressed in white adipocytes but downregulated in obesity and insulin resistance. In this study, it was found that tumor necrosis factor α (TNFα) and other pro-inflammatory cytokines contribute to the downregulation of SIK2 during inflammation. The involvement of IKK in SIK2 regulation was also observed. Understanding the downregulation of SIK2 during inflammation could help in developing strategies to restore its expression in insulin resistance.
SCIENTIFIC REPORTS
(2023)
Article
Biochemistry & Molecular Biology
Darshan Joshi, Rajesh Bahekar, Shubhangi Soman, Pradip Jadav, Dipam Patel, Amitgiri Goswami, Jignesh Pethani, Jeevan Kumar, Jitendra Patel, Rajesh Sundar, Poonamgiri Goswami, Krishnarup Goshdastidar, Hoshang Patel, Ankit Patel, Debdutta Bandyopadhyay, Abhijit Chattarjee, Manoranjan Sharma, Mukul Jain, Ranjit Desai
Summary: In this study, novel structural optimizations were conducted to discover effective Bruton's Tyrosine Kinase (BTK) inhibitors for the treatment of autoimmune disorders. Compound 14b was identified as a potent and selective BTK inhibitor with improved oral bioavailability. It displayed strong efficacy in in vitro and in vivo assays, making it a viable therapeutic option for autoimmune disorders.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Alejandro Diaz-Holguin, Azam Rashidian, Dirk Pijnenburg, Glaucio Monteiro Ferreira, Alzbeta Stefela, Miroslav Kaspar, Eva Kudova, Antti Poso, Rinie van Beuningen, Petr Pavek, Thales Kronenberger
Summary: This article investigates the conformational changes induced by FXR antagonists 2a and 2h using microsecond molecular dynamics simulations. The study reveals that the antagonists can influence the conformations of different FXR regions and cause changes in the heterodimerization interface, thereby affecting the activation and recruitment of coactivators and corepressors.
Article
Genetics & Heredity
Bruna Los, Glaucio Monteiro Ferreira, Jessica Bassani Borges, Thales Kronenberger, Victor Fernandes de Oliveira, Carolina Dagli-Hernandez, Raul Hernandes Bortolin, Rodrigo Marques Goncalves, Andre Arpad Faludi, Augusto Akira Mori, Thais Kristini Almendros Barbosa, Renata Caroline Costa de Freitas, Cinthia Elim Jannes, Alexandre da Costa Pereira, Gisele Medeiros Bastos, Antti Poso, Rosario Dominguez Crespo Hirata, Mario Hiroyuki Hirata
Summary: This study investigates the effects of PCSK9 missense variants on protein structure and interactions with LDLR. The findings suggest that these variants disrupt intra-molecular interactions essential for PCSK9 structural conformation and biological activity, potentially contributing to the development of Familial Hypercholesterolemia.
Review
Pharmacology & Pharmacy
Thales Kronenberger, Stefan A. Laufer, Thanigaimalai Pillaiyar
Summary: This article discusses the rationale for inhibitors targeting SARS-CoV-2 Mpro. Small molecules and peptidomimetic inhibitors are two types of inhibitors with different modes of action. Novel inhibitors discovered during the COVID-19 pandemic are highlighted, focusing on their binding modes and structures.
DRUG DISCOVERY TODAY
(2023)
Article
Chemistry, Medicinal
Marcel Rak, Roberta Tesch, Lena M. Berger, Ekaterina Shevchenko, Monika Raab, Amelie Tjaden, Rezart Zhubi, Dimitrios-Ilias Balourdas, Andreas C. Joerger, Antti Poso, Andreas Kra, Lewis Elson, Aleksandar Luc, Thales Kronenberger, Thomas Hanke, Klaus Strebhardt, Mourad Sanhaji, Stefan Knapp
Summary: Salt-inducible kinases 1-3 (SIK1-3) are important regulators of cellular homeostasis. This study presents a structure-based approach to improve the selectivity of inhibitors targeting SIK kinases, resulting in the development of a valuable tool compound, MR22, which showed excellent selectivity and phenotypic effects in ovarian cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Han Wee Ong, Anna Truong, Frank Kwarcinski, Chandi de Silva, Krisha Avalani, Tammy M. Havener, Michael Chirgwin, Kareem A. Galal, Caleb Willis, Andreas Kramer, Shubin Liu, Stefan Knapp, Emily R. Derbyshire, Reena Zutshi, David H. Drewry
Summary: Malaria is a global health problem with high morbidity and mortality rates. The emergence of drug resistance against current treatments emphasizes the need for alternative antimalarials. In this study, we discovered Ki8751 as an inhibitor of essential kinase PfPK6 and identified two compounds (67 and 79) with potent antiplasmodial activity against both blood and liver stages of malaria.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Review
Biochemistry & Molecular Biology
Maria Mushtaq Ali, Sehrish Naz, Sajda Ashraf, Stefan Knapp, Zaheer Ul-Haq
Summary: BRD9 inhibitors have potential therapeutic value in cancer treatment by selectively targeting BRD9 and BRD7 proteins, regulating chromatin structure and gene expression, and inhibiting tumor growth and progression.
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
(2023)
Article
Biochemistry & Molecular Biology
Martin P. Schwalm, Stefan Knapp, Vladimir V. Rogov
Summary: Induction of LC3/GABARAP protein interactions with target proteins by small molecules has the potential for targeted protein degradation, but no potent ligands have been developed despite intensive screening campaigns in the past 5 years, limiting its therapeutic applications.
JOURNAL OF CELLULAR BIOCHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ivana Mejdrova, Jan Dusek, Krystof Skach, Alzbeta Stefela, Josef Skoda, Karel Chalupsky, Klara Dohnalova, Ivona Pavkova, Thales Kronenberger, Azam Rashidian, Lucie Smutna, Vojtech Duchoslav, Tomas Smutny, Petr Pavek, Radim Nencka
Summary: The nuclear constitutive androstane receptor (CAR, NR1I3) plays significant roles in hepatic functions and has been proposed as a target for metabolic or liver disease therapy. However, current CAR agonists have limited selectivity. We discovered derivatives that directly activate human CAR and are selective, non-toxic, and show in vivo activity, highlighting CAR as a therapeutic target.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Teodor Dimitrov, Athina Anastasia Moschopoulou, Lennart Seidel, Thales Kronenberger, Mark Kudolo, Antti Poso, Christian Geibel, Pascal Woelffing, Daniel Dauch, Lars Zender, Dieter Schollmeyer, Juergen Bajorath, Michael Forster, Stefan Laufer
Summary: The ATM kinase is an important regulator of the cellular response to DNA double-strand breaks and is considered a promising target in cancer treatment. This study introduces a new class of specific benzimidazole-based ATM inhibitors with high potency against the isolated enzyme and favorable selectivity within related kinases. These inhibitors show strong enzymatic and cellular activities, as well as promising pharmacokinetic properties and selectivities within the PIKK and PI3K families.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Jun Yong Choi, Yoshihiko Noguchi, James M. Alburger, Simon Bayle, Eugene Chung, Wayne Grant, Apirat Chaikuad, Stefan Knapp, Derek R. Duckett, William R. Roush
Summary: Inhibiting a single kinase isoform is difficult due to the similarity of ATP-binding sites. Through studying crystal structures, a highly selective inhibitor for CK1 & epsilon; (SR-4133) was developed. The mismatch between SR-4133 and CK1 & delta; destabilizes their interaction, while the hydrophobic surface of CK1 & epsilon; enhances the binding of SR-4133, leading to selective inhibition. These potent CK1 & epsilon;-selective inhibitors exhibit nanomolar growth inhibition in bladder cancer cells and inhibit the phosphorylation of 4E-BP1, a downstream effector of CK1 & epsilon;.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Emmanuel Deau, Mattias F. F. Lindberg, Freideiric Miege, Didier Roche, Nicolas George, Pascal George, Andreas Kra''mer, Stefan Knapp, Laurent Meijer
Summary: Dual-specificity,tyrosine phosphorylation-regulated kinases (DYRKs) and cdc2-like kinases (CLKs) have been identified as important targets for various pathologies. In this study, a family of DYRK/CLK inhibitors called Leucettinibs, derived from Leucettines and Leucettamine B, were synthesized and characterized. These inhibitors showed subnanomolar IC50 on DYRK1A and demonstrated potential for therapeutic drug development. Kinase-inactive isomers, iso-Leucettinibs, were also synthesized as suitable negative control compounds. Leucettinibs were found to inhibit DYRK1A substrate phosphorylation in cells.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Organic
Xiaodan Ouyang, Paul M. D'Agostino, Matti Wahlsten, Endrews Delbaje, Jouni Jokela, Perttu Permi, Greta Gaiani, Antti Poso, Piia Bartos, Tobias A. M. Gulder, Hannu Koistinen, David P. Fewer
Summary: In this study, a comparative bioinformatic analysis was used to identify radiosumin biosynthetic gene clusters in the genomes of 13 filamentous cyanobacteria. The entire biosynthetic gene cluster was captured and expressed in Escherichia coli. High-resolution liquid chromatography-mass spectrometry, nuclear magnetic resonance spectroscopy, and chemical degradation analysis revealed the chemical structure of novel radiosumins produced by cyanobacteria. Radiosumin C was found to inhibit human trypsin isoforms selectively.
ORGANIC & BIOMOLECULAR CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Karoline B. Waitman, Larissa C. de Almeida, Marina C. Primi, Jorge A. E. G. Carlos, Claudia Ruiz, Thales Kronenberger, Stefan Laufer, Marcia Ines Goettert, Antti Poso, Sandra V. Vassiliades, Vinicius A. M. de Souza, Monica F. Z. J. Toledo, Neuza M. A. Hassimotto, Michael D. Cameron, Thomas D. Bannister, Leticia Costa-Lotufo, Joa o A. Machado-Neto, Mauricio T. Tavares, Roberto Parise-Filho
Summary: A series of hybrid inhibitors combining pharmacophores of known kinase inhibitors and benzohydroxamate HDAC inhibitors were synthesized and evaluated for their anticancer activity and pharmacokinetic properties. Compounds 4d-f exhibited promising cytotoxicity against hematological cells and moderate activity against solid tumor models. Compound 4d showed potent inhibition of multiple kinase targets and had stable interactions with HDAC and members of the JAK family. These compounds showed selective cytotoxicity with minimal effects on non-tumorigenic cells and favorable pharmacokinetic profiles.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2024)