Article
Chemistry, Medicinal
Yue Pan, Mary M. Mader
Summary: This article introduces allosteric inhibition of kinases, summarizes the discovery of allosteric MEK1/2 and BCR-ABL1 inhibitors, and discusses the approaches to screening and validating allosteric inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Victor W. Mak, Akash M. Patel, Rose Yen, Jennifer Hanisak, Yeon-Hee Lim, Jianming Bao, Rong Zheng, W. Michael Seganish, Yang Yu, David R. Healy, Aimie Ogawa, Zhao Ren, Aileen Soriano, Grigori P. Ermakov, Maribel Beaumont, Essam Metwally, Alan C. Cheng, Andreas Verras, Thierry Fischmann, Matthias Zebisch, H. Leonardo Silvestre, Paul A. McEwan, John Barker, Paul Rearden, Thomas J. Greshock
Summary: Activation of PKG1 alpha is a promising approach for treating cardiovascular diseases, as it induces various beneficial effects such as smooth muscle relaxation and prevention of platelet aggregation. In this study, small molecule activators were optimized and shown to have anti-proliferative effects in human pulmonary arterial smooth muscle cells. Mechanistic studies revealed that the activators work through a similar mechanism as cGMP and bind to an allosteric pocket in close proximity to the cyclic nucleotide-binding domain.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Xinyu Xu, Jeremy Shonberg, Jonas Kaindl, Mary J. J. Clark, Anne Stoessel, Luis Maul, Daniel Mayer, Harald Huebner, Kunio Hirata, A. J. Venkatakrishnan, Ron O. O. Dror, Brian K. K. Kobilka, Roger K. K. Sunahara, Xiangyu Liu, Peter Gmeiner
Summary: Constrained catecholamines exhibit high selectivity for the beta(2)AR due to reduced ligand flexibility and a less stable binding pocket in the beta(1)AR. Surrounding residues in the extracellular loops (ECLs) of the receptors allosterically modify the binding pocket, resulting in different affinity and selectivity for the beta(2)AR. Exploiting these allosteric influences may lead to the development of more subtype-selective GPCR ligands.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Aleksandra Levina, Kaelin D. Fleming, John E. Burke, Thomas A. Leonard
Summary: This study elucidates the mechanism of self-activation of 3-phosphoinositide-dependent kinase 1 (PDK1). It is activated by dimerization mediated by PIP3 and trans-autophosphorylation, while its PH domain inhibits its activity. These results suggest that phosphoinositide-dependent activation may also apply to various effector kinases.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Medicinal
Oliver Laufkoetter, Huabin Hu, Filip Miljkovic, Juergen Bajorath
Summary: Allosteric kinase inhibitors are highly selective and promising candidates for kinase drug discovery. Exploring allosteric mechanisms is of great interest in basic research and drug design. X-ray structures of kinase complexes have provided valuable data for identifying and characterizing allosteric inhibitors. This study presents a comprehensive survey of allosteric kinase inhibitors and activators based on publicly available X-ray structures, mapping their binding sites and distribution in kinase binding pockets. The structural features of these compounds are discussed, and active structural analogues and high-confidence target annotations are identified, suggesting additional activities for some allosteric inhibitors.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Paul Tawa, Lei Zhang, Essam Metwally, Yan Hou, Mark A. McCoy, W. Michael Seganish, Rumin Zhang, Emily Frank, Payal Sheth, Jennifer Hanisak, Christopher Sondey, David Bauman, Aileen Soriano
Summary: cGMP-dependent protein kinase (PKG) is an important drug target for cardiovascular diseases. In this study, a novel series of activators were identified that can directly bind and enhance the kinase activity of PKG1. These activators mimic the effect of cGMP on PKG1 by modulating its kinetic parameters and binding affinity for cGMP. They act by binding to an allosteric site near the regulatory domain of PKG1.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biology
Atilio Reyes Romero, Serjey Lunev, Grzegorz M. Popowicz, Vito Calderone, Matteo Gentili, Michael Sattler, Jacek Plewka, Michal Taube, Maciej Kozak, Tad A. Holak, Alexander S. S. Domling, Matthew R. Groves
Summary: Romero et al. conducted NMR-based screening of 1500 fragments to identify those binding at the oligomeric interface of malate dehydrogenase (MDH). Their study indicates an allosteric mechanism affecting enzymatic activity, paving the way for development of more selective molecules and serving as a starting point for future specific MDH inhibitor development.
COMMUNICATIONS BIOLOGY
(2021)
Article
Chemistry, Multidisciplinary
Joerg Benz, Arne C. Rufer, Sylwia Huber, Andreas Ehler, Melanie Hug, Andreas Topp, Wolfgang Guba, Eva Carolina Hofmann, Ravi Jagasia, Rosa Maria Rodriguez Sarmiento
Summary: This study identified a new class of GCase activators with specific binding mode, which may enhance substrate metabolism in lysosomes and have potential therapeutic implications for Parkinson's disease and Gaucher's disease. The findings provide important insights for future drug discovery efforts in the field of GCase activation.
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
(2021)
Article
Chemistry, Multidisciplinary
Pratik Rajesh Chheda, Grant T. Cooling, Sondra F. Dean, Jonah Propp, Kathryn F. Hobbs, M. Ashley Spies
Summary: One of the challenges in drug design is targeting cryptic allosteric pockets in enzyme targets, which can provide the best option for drug development. Using computational and experimental methods, a successful approach has been presented in rationally exploiting the cryptic allosteric pocket of H. pylori glutamate racemase, leading to the discovery of a series of natural product allosteric inhibitors. These studies reveal the source of allosteric inhibition and how protein-ligand binding affects enzyme dynamics.
COMMUNICATIONS CHEMISTRY
(2021)
Review
Biochemistry & Molecular Biology
Alejandro E. Leroux, Ricardo M. Biondi
Summary: This review presents the molecular mechanisms of protein kinase PDK1 in phosphorylating different substrates, including the colocalization with Akt/PKB and the interaction between the hydrophobic motif of substrates and the PIF-pocket of PDK1. The distinct conformations of full-length PDK1 also influence the interaction and phosphorylation of substrates.
BIOCHEMICAL JOURNAL
(2023)
Article
Cell Biology
Terry Kenakin
Summary: Signaling bias is a phenomenon in seven transmembrane receptors where different agonists can activate specific signaling pathways more than others, potentially leading to therapeutic benefits. However, determining a quantitative value for receptor bias that can be translated to useful in vivo studies remains a challenge, and further research is needed to overcome current limitations.
CELLULAR SIGNALLING
(2021)
Article
Biochemistry & Molecular Biology
Yan Lu, Hongyue Liu, Dehua Yang, Li Zhong, Ye Xin, Suwen Zhao, Ming-Wei Wang, Qingtong Zhou, Wenqing Shui
Summary: The use of affinity mass spectrometry (MS) for screening negative allosteric modulators (NAMs) of GPCR targets offers advantages in reducing protein and compound consumption and speeding up data acquisition. The newly identified NAM through this method exhibits a unique binding mode and antagonistic property different from known NAMs, showcasing its potential for guiding the design of novel allosteric modulators targeting class A GPCRs.
ACS CHEMICAL BIOLOGY
(2021)
Review
Pharmacology & Pharmacy
Morgane Mannes, Charlotte Martin, Christel Menet, Steven Ballet
Summary: Allosteric modulation, particularly with peptides, is an emerging approach in drug design and discovery, holding great promise for modulating protein function and advancing therapeutic development.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Jung Ah Byun, Bryan VanSchouwen, Nishi Parikh, Madoka Akimoto, Eric Tyler McNicholl, Giuseppe Melacini
Summary: Allosteric pluripotency is a phenomenon where an allosteric effector switches from an agonist to an antagonist under experimental conditions. In the case of PKA, this pluripotency arises from divergent allosteric responses of two homologous tandem cAMP-binding domains, with the key drivers of this switch not fully understood. Understanding these drivers, such as state-selective frustration, is crucial for the design of effective allosteric therapeutics.
Article
Chemistry, Multidisciplinary
Yang Liu, Qiang Guo, Heng Yang, Xiao-Wen Zhang, Na Feng, Jing-Kang Wang, Ting-Ting Liu, Ke-Wu Zeng, Peng-Fei Tu
Summary: This study reveals that knockdown of IGF2BP1 induces cancer cell apoptosis, activates immune cell infiltration, and decreases PD-L1 expression in hepatocellular carcinoma. The study also identifies CuB as a small-molecule inhibitor of IGF2BP1, which blocks its recognition of m(6)A mRNA targets and exhibits anti-cancer effects.
ACS CENTRAL SCIENCE
(2022)
Article
Biochemistry & Molecular Biology
Suresh Velnati, Sara Centonze, Federico Girivetto, Daniela Capello, Ricardo M. Biondi, Alessandra Bertoni, Roberto Cantello, Beatrice Ragnoli, Mario Malerba, Andrea Graziani, Gianluca Baldanzi
Summary: PKC zeta and PKC iota/lambda form the atypical protein kinase C subgroup, characterized by their regulation distinct from conventional PKCs. Both PKC zeta and PKC iota interact with phosphatidic acid and phosphatidylserine, while PKC iota uniquely binds to phosphatidylinositol-monophosphates. Additionally, phosphatidylinositol 4-phosphate specifically activates PKC iota, indicating a specific regulation of PKC iota by certain membrane lipids.
Article
Chemistry, Medicinal
Markus Hartmann, Jessica Huber, Jan S. Kramer, Jan Heering, Larissa Pietsch, Holger Stark, Dalibor Odadzic, Iris Bischoff, Robert Fuerst, Martin Schroeder, Masato Akutsu, Apirat Chaikuad, Volker Doetsch, Stefan Knapp, Ricardo M. Biondi, Vladimir V. Rogov, Ewgenij Proschak
Summary: The study revealed that the human Atg8 family proteins LC3A and LC3B can be inhibited by the small molecule novobiocin, laying the foundation for the development of more potent chemical probes and potential applications in autophagy-mediated degraders. This study also reports the first nonpeptide inhibitors for these protein interaction targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Hematology
Afsar Ali Mian, Isabella Haberbosch, Hazem Khamaisie, Abed Agbarya, Larissa Pietsch, Elizabeh Eshel, Dally Najib, Claudia Chiriches, Oliver Gerhard Ottmann, Oliver Hantschel, Ricardo M. Biondi, Martin Ruthardt, Jamal Mahajna
Summary: The study found that crizotinib can effectively inhibit the growth of Ph+ leukemia cells without affecting Ph- cells. Its efficacy has been validated in different models, demonstrating a unique dual mechanism of action.
ANNALS OF HEMATOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Georg Dultz, Sanjay K. Srikakulam, Michael Konetschnik, Tetsuro Shimakami, Nadezhda T. Doncheva, Julia Dietz, Christoph Sarrazin, Ricardo M. Biondi, Stefan Zeuzem, Robert Tampe, Olga Kalinina, Christoph Welsch
Summary: The Q80K polymorphism in the NS3-4A protease of hepatitis C virus is associated with treatment failure of direct acting antiviral agents and is highly prevalent in genotype 1a infections. This polymorphism destabilizes protease protein fold and reduces peptide substrate turnover. Epistatic substitutions at residues 91 and 174 stabilize the protein fold but inversely correlate with enzymatic activity, contributing to viral fitness through mechanisms not directly related to RNA replication.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Dina Aboushady, Sari S. Rasheed, Jennifer Herrmann, Ahmed Maher, Ebaa M. El-Hossary, Eslam S. Ibrahim, Ashraf H. Abadi, Matthias Engel, Rolf Mueller, Mohammad Abdel-Halim, Mostafa M. Hamed
Summary: Novel compounds with potent antibacterial activity have been designed and synthesized, showing the ability to inhibit a range of bacteria, including resistant strains, while maintaining a good safety profile.
BIOORGANIC CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Yasmeen T. AlNajjar, Moustafa Gabr, Ahmed K. ElHady, Mohamed Salah, Gerrit Wilms, Ashraf H. Abadi, Walter Becker, Mohammad Abdel-Halim, Matthias Engel
Summary: The study found that dual inhibitors with higher selectivity for Dyrk1A and inhibition of alpha-synuclein aggregation present a potential novel therapeutic strategy for Parkinson's disease. Compound b27, displaying the highest inhibitory potency and selectivity, could be a promising drug candidate for PD treatment.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Sarah H. Megahed, Sari Rasheed, Jennifer Herrmann, Ebaa M. El-Hossary, Yahia I. El-Shabrawy, Ashraf H. Abadi, Matthias Engel, Rolf Mueller, Mohammad Abdel-Halim, Mostafa M. Hamed
Summary: The resistance of bacteria to current antibiotics necessitates the development of new antibacterial agents that are safe and effective against multi-drug resistant strains. Compound I has been identified as a promising candidate with broad-spectrum antibacterial activity and low cytotoxicity. In this study, we further optimized Compound I by modifying the benzenoid part and substituents at positions 6 and 7. The resulting compounds showed significant antibacterial activity against pathogenic bacteria, including drug-resistant strains. Compound 12 exhibited 2-4 times improvement in activity compared to Compound I against specific bacteria, and these compounds were also found to be safe for human cells.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Chemistry, Medicinal
Dalia S. El-Gamil, Ahmed K. ElHady, Po-Jen Chen, Tsong-Long Hwang, Ashraf H. Abadi, Mohammad Abdel-Halim, Matthias Engel
Summary: In this study, a novel series of potent and selective Clk1/4 inhibitors were discovered and characterized. These inhibitors show promising anti-cancer activities and have the potential to be used in clinical settings.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Medicine, Research & Experimental
Suzan Fangary, Mohammad Abdel-Halim, Reem K. Fathalla, Raghda Hassan, Noha Farag, Matthias Engel, Samar Mansour, Salma N. Tammam
Summary: This article presents a method for achieving selective drug delivery and reducing toxicity through nanoparticle-loaded liposomes. By adjusting the uptake of nanoparticles in bacterial cells and mammalian cells, the antibacterial actions can be enhanced while minimizing toxicity to mammalian cells.
MOLECULAR PHARMACEUTICS
(2022)
Article
Chemistry, Medicinal
Sarah S. Darwish, Po-Jen Chen, Mostafa M. Hamed, Reem A. Wagdy, Shun-Hua Chen, Ashraf H. Abadi, Mohammad Abdel-Halim, Tsong-Long Hwang, Matthias Engel
Summary: This study developed new drugs that selectively inhibit the activation of NF-kappa B in macrophages, which may help treat inflammatory diseases with fewer side effects.
Article
Biochemistry & Molecular Biology
Reem A. Wagdy, Po-Jen Chen, Mostafa M. Hamed, Sarah S. Darwish, Shun-Hua Chen, Ashraf H. Abadi, Mohammad Abdel-Halim, Tsong-Long Hwang, Matthias Engel
Summary: We designed and synthesized novel NF-kappa B inhibitors, which showed potential applications in suppressing cytokine release and selectively depleting macrophages.
BIOORGANIC CHEMISTRY
(2022)
Review
Chemistry, Medicinal
Ahmed K. ElHady, Dalia S. El-Gamil, Ashraf H. Abadi, Mohammad Abdel-Halim, Matthias Engel
Summary: Clk1 has been identified as a promising target for the treatment of various diseases, especially those related to deregulated alternative splicing. Clinical trials of small molecule inhibitors targeting Clk1 are underway for the treatment of solid cancer, which is promoted by oncogenic protein variants derived from alternative splicing. In addition, Clk1 has been implicated in the progression of Alzheimer's disease. However, most Clk1 inhibitors lack sufficient selectivity, affecting other Clk isoforms and Dyrk kinases.
MEDICINAL RESEARCH REVIEWS
(2023)
Article
Chemistry, Medicinal
Dalia S. El-Gamil, Ahmed K. ElHady, Po-Jen Chen, Tsong-Long Hwang, Ashraf H. Abadi, Mohammad Abdel-Halim, Matthias Engel
Summary: Clk1 kinase is a key modulator of pre-mRNA alternative splicing and could be a potential target for treating various tumors, Duchenne's muscular dystrophy, and viral infections. A new 5-methoxybenzothiophene scaffold was developed, enabling selective inhibition of Clk1 among isoenzymes. The derivatives 26a and 27a showed unprecedented selectivity and good growth inhibitory activity in cancer cells.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Reem K. Fathalla, Wolfgang Froehner, Chantal D. Bader, Patrick D. Fischer, Charlotte Dahlem, Deep Chatterjee, Sebastian Mathea, Alexandra K. Kiemer, Haribabu Arthanari, Rolf Muller, Mohammad Abdel-Halim, Christian Ducho, Matthias Engel
Summary: This study reports a novel class of reversible MurA inhibitors that can inhibit both wild type MurA and fosfomycin-resistant MurA C115D mutant, showing potential for inhibiting cell wall synthesis. The most potent inhibitor 46 exhibits good stability and non-toxicity.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Reem K. Fathalla, Matthias Engel, Christian Ducho
Summary: 8-Anilinonaphthalene-1-sulfonic acid (ANS) is a fluorescent probe commonly used to detect conformational changes in proteins. This study discovered that ANS can inhibit the activity of various isoforms of MurA and identified a more potent ANS analog. These findings highlight the potential of targeting the ANS binding pocket for the development of antibiotics.
ARCHIV DER PHARMAZIE
(2023)