Article
Chemistry, Medicinal
Feifei Wu, Huiyu Li, Qi An, Yaoliang Sun, Jinghua Yu, Wenting Cao, Pu Sun, Xingxing Diao, Linghua Meng, Shilin Xu
Summary: HPK1 is a potential therapeutic target for cancer immunotherapy as a negative regulator of TCR signaling. In this study, a series of HPK1 inhibitors with a 7H-pyrrolo[2,3-d]pyrimidine scaffold were designed and synthesized, among which compound 31 showed potent inhibitory activity and favorable selectivity. These findings provide new insights for further optimization and development of HPK1 inhibitors for cancer immunotherapy.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Qiangsheng Zhu, Nannan Chen, Xinjian Tian, Yeling Zhou, QiDong You, Xiaoli Xu
Summary: HPK1, a negative regulator of immune cells, has emerged as a promising target for tumor immunotherapy. Inhibitors and PROTACs targeting HPK1 have been developed to enhance immune response and inhibit tumor growth.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biology
Jin-Min Sun, Hong-Ye Fan, Yan Zhu, Ting-Ting Pan, Yong-Ping Wu, Dao-Yong Zhang, Xiao-Yu Hou
Summary: MAP4K1 is highly expressed in glioma cells of human GBM specimens and is associated with poor prognosis. Silencing MAP4K1 inhibits GBM cell proliferation and glioma growth. MAP4K1 modulates cytokine-chemokine networks and impairs T-cell migration and infiltration.
LIFE SCIENCE ALLIANCE
(2023)
Article
Chemistry, Medicinal
Alexander Sokolsky, Oleg Vechorkin, Joshua R. Hummel, Evan D. Styduhar, Anlai Wang, Minh H. Nguyen, Hai Fen Ye, Kai Liu, Ke Zhang, Jun Pan, Qinda Ye, Onur Atasoylu, Elham Behshad, Xin He, Patricia Conlen, Kristine Stump, Min Ye, Sharon Diamond, Maryanne Covington, Swamy Yeleswaram, Wenqing Yao
Summary: A novel biaryl amide series has been discovered as selective inhibitors of HPK1, showing outstanding enzymatic and cellular potency and encouraging kinome selectivity.
ACS MEDICINAL CHEMISTRY LETTERS
(2023)
Article
Biochemistry & Molecular Biology
Junjie Zhang, Yan Li, Haotian Tang, Qianqian Zhou, Linjiang Tong, Jian Ding, Hua Xie, Bing Xiong, Tongchao Liu
Summary: A novel series of HPK1 inhibitors were developed and evaluated for their potential in cancer immunotherapy. The most promising compound, 10n, showed significant inhibition of HPK1 and selectivity over other kinases, making it a potential lead compound for further development.
BIOORGANIC CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Andrew P. Degnan, Godwin K. Kumi, Christopher W. Allard, Erika Araujo, Walter L. Johnson, Kurt Zimmermann, Bradley C. Pearce, Steven Sheriff, Alan Futran, Xin Li, Gregory A. Locke, Dan You, John Morrison, Karen E. Parrish, Caitlyn Stromko, Anwar Murtaza, Jinqi Liu, Benjamin M. Johnson, Gregory D. Vite, Mark D. Wittman
Summary: The study presents a novel HPK1 inhibitor which, when used in combination in a colorectal cancer model, significantly enhances the efficacy of anti-PD1 treatment.
ACS MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Bryan K. Chan, Eileen Seward, Michael Lainchbury, Thomas F. Brewer, Le An, Toby Blench, Matthew W. Cartwright, Grace Ka Yan Chan, Edna F. Choo, Jason Drummond, Richard L. Elliott, Emanuela Gancia, Lewis Gazzard, Baihua Hu, Graham E. Jones, Xifeng Luo, Andrew Madin, Sushant Malhotra, John G. Moffat, Jodie Pang, Laurent Salphati, Christopher J. Sneeringer, Craig E. Stivala, Binqing Wei, Weiru Wang, Ping Wu, Timothy P. Heffron
Summary: HPK1, identified as a negative regulator of T-cell activation, has potential implications in tumor therapy. Through structure-based drug design, a series of small molecule inhibitors of HPK1 were discovered with significantly improved kinase selectivity, showing potential therapeutic value in tumor treatment.
ACS MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Cell Biology
James S. Chavez, Jennifer L. Rabe, Katia E. Nino, Harrison H. Wells, Rachel L. Gessner, Taylor S. Mills, Giovanny Hernandez, Eric M. Pietras
Summary: Chronic inflammation, seen in aging and diseases such as diabetes and obesity, can lead to hematological malignancy. In this study, the role of the transcription factor PU.1 in regulating hematopoietic activity under chronic inflammation was investigated using a PU.1-deficient mouse model. The results showed that PU.1 is critical in restraining inflammatory myelopoiesis and suppressing cell cycle and self-renewal gene programs in myeloid-biased multipotent progenitor (MPP) cells. These findings highlight the importance of PU.1 in regulating emergency myelopoiesis and its relevance to inflammatory diseases and leukemogenesis.
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Sven Malchow, Alla Korepanova, Sanjay C. Panchal, Ryan A. McClure, Kenton L. Longenecker, Wei Qiu, Hongyu Zhao, Min Cheng, Jun Guo, Kelly L. Klinge, Patricia Trusk, Steven D. Pratt, Tao Li, Matthew D. Kurnick, Lishu Duan, Alex R. Shoemaker, Sujatha M. Gopalakrishnan, Scott E. Warder, J. Brad Shotwell, Albert Lai, Chaohong Sun, Augustine T. Osuma, William N. Pappano
Summary: HPK1 is a member of the MAP4K family and plays a dominant role in negatively regulating T cell function, making it a potential target for immune therapy. The discovery of the selective and potent HPK1 chemical probe, A-745, demonstrates its ability to activate immune cells similar to HPK1-deficient T cells.
ACS CHEMICAL BIOLOGY
(2022)
Article
Multidisciplinary Sciences
Hyun-Kyoung Lim, Sungjun Bae, Kayoung Han, Bok-Man Kang, Yoonyi Jeong, Seong-Gi Kim, Minah Suh
Summary: Cerebral hypoperfusion is a potential cause of postictal neurological dysfunction in epilepsy. The reduction in cerebral blood flow (CBF) after a seizure is initially induced by arteriolar constriction, and then prolonged by neutrophil adhesion to brain capillaries, decreased red blood cell (RBC) flow, and elevated ICAM-1 expression. Antibodies against Ly6G and LFA-1 can prevent neutrophil adhesion and restore CBF to normal levels. Seizure-induced neutrophil adhesion via ICAM-1 may contribute to the prolonged hypoperfusion and neurological dysfunction in epilepsy.
Article
Chemistry, Medicinal
Huanyu Shi, Haotian Tang, Yan Li, Danqi Chen, Tongchao Liu, Yuting Chen, Xin Wang, Lin Chen, Ying Wang, Hua Xie, Bing Xiong
Summary: In this study, a series of potent HPK1 inhibitors with quinazoline-2,5-diamine scaffold were designed, synthesized and evaluated. The most potent compound 9h was identified, which exhibited strong inhibition of downstream phosphorylation, enhanced interleukin-2 (IL-2) production, and reversed prostaglandin E2 (PGE2)-induced immune suppression. This research not only provided a tool compound for studying HPK1 pharmacology, but also served as a reliable reference for the development of HPK1 inhibitors.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Biochemical Research Methods
Wai L. Lau, Bradley Pearce, Heather Malakian, Iyoncy Rodrigo, Dianlin Xie, Mian Gao, Frank Marsilio, Chiehying Chang, Max Ruzanov, Jodi K. Muckelbauer, John A. Newitt, Dasa Lipovsek, Steven Sheriff
Summary: This study utilized yeast surface display to select HPK1 kinase-domain variants with improved expression level and solubility, leading to successful crystallization and valuable insights for drug design.
ACTA CRYSTALLOGRAPHICA SECTION F-STRUCTURAL BIOLOGY COMMUNICATIONS
(2021)
Article
Immunology
Almke Bader, Michael Winkelmann, Ignasi Forne, Barbara Walzog, Daniela Maier-Begandt
Summary: The signaling pathways involving beta(2) integrins, TCRs, and BCRs have similar mechanisms, but can have opposing effects. HPK1, for example, negatively regulates T and B cell activation but promotes neutrophil adhesion. The interactions of HPK1 with other proteins in different leukocyte subsets play a key role in these processes.
EUROPEAN JOURNAL OF IMMUNOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Yang Liu, Renjie Song, Lu Zhao, Zhike Lu, Yini Li, Xinyi Zhan, Fengjiao Lu, Jiang Yang, Yamei Niu, Xuetao Cao
Summary: This study reveals the important role of ALKBH5 in enhancing the intrinsic ability of neutrophil migration for antibacterial innate defense. Deficiency of ALKBH5 results in impaired neutrophil migration, leading to increased mortality and proinflammatory cytokine production in mice with polymicrobial sepsis. Mechanistically, ALKBH5 regulates protein expression of neutrophil migration-related molecules by altering RNA decay, thereby empowering neutrophils with high migration capability.
SIGNAL TRANSDUCTION AND TARGETED THERAPY
(2022)
Article
Biochemistry & Molecular Biology
Robert S. Hagan, John C. Gomez, Jose Torres-Castillo, Jessica R. Martin, Claire M. Doerschuk
Summary: Bacterial pneumonia leads to the recruitment and activation of neutrophils and macrophages in the lung, which contribute to antibacterial defenses. TBK1, a protein with multiple functions, is found to play a role in antibacterial defenses in the lung apart from its known functions. TBK1 deficiency leads to impaired bacterial clearance and survival, and lower cytokine expression in the infected lung. Neutrophils, but not macrophages, are identified as the key TBK1-dependent cell type in this process.
AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY
(2022)
Article
Cardiac & Cardiovascular Systems
Roland Immler, Wiebke Nadolni, Annika Bertsch, Vasilios Morikis, Ina Rohwedder, Sergi Masgrau-Alsina, Tobias Schroll, Anna Yevtushenko, Oliver Soehnlein, Markus Moser, Thomas Gudermann, Eytan R. Barnea, Markus Rehberg, Scott Simon, Susanna Zierler, Monika Pruenster, Markus Sperandio
Summary: This study reveals the critical role of the voltage-gated potassium channel K(V)1.3 in calcium signaling and neutrophil trafficking during acute inflammatory processes. The findings provide evidence for the involvement of K(V)1.3 in key functions of neutrophils and suggest new therapeutic approaches for treating inflammatory disorders.
CARDIOVASCULAR RESEARCH
(2022)
Review
Biochemistry & Molecular Biology
Piero Portincasa, Leonilde Bonfrate, Mirco Vacca, Maria De Angelis, Ilaria Farella, Elisa Lanza, Mohamad Khalil, David Q. -H. Wang, Markus Sperandio, Agostino Di Ciaula
Summary: The gut microbiota consists of trillions of commensal microorganisms including bacteria, fungi, and viruses, which coexist in symbiosis with the host and have profound effects on human health. Short chain fatty acids (SCFAs) are the most abundant bacterial metabolites in the human body and play an important role in metabolic, endocrine, and immune functions. Diet can influence the composition and activity of the gut microbiota, as well as SCFAs production and metabolic effects.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Chemistry, Multidisciplinary
Tarik Bozoglu, Seungmin Lee, Tilman Ziegler, Victoria Jurisch, Sanne Maas, Andrea Baehr, Rabea Hinkel, Amelie Hoenig, Anjana Hariharan, Christina Inyeop Kim, Simon Decker, Haider Sami, Tobias Koppara, Ruppert Oellinger, Oliver J. Muller, Derk Frank, Remco Megens, Peter Nelson, Christian Weber, Angelika Schnieke, Markus Sperandio, Gianluca Santamaria, Roland Rad, Alessandra Moretti, Karl-Ludwig Laugwitz, Oliver Soehnlein, Manfred Ogris, Christian Kupatt
Summary: The study demonstrates a method of retargeting adeno-associated viruses (AAVs) to endothelial cells by coating them with second-generation polyamidoamine dendrimers (G2) linked to endothelial-affine peptides (CNN). This approach improves gene transfer efficiency, potentially enabling applications in vascular and atherosclerosis models.
Article
Hematology
Qiuyue Ma, Roland Immler, Monika Pruenster, Markus Sellmayr, Chenyu Li, Albrecht von Brunn, Brigitte von Brunn, Rosina Ehmann, Roman Woelfel, Matteo Napoli, Qiubo Li, Paola Romagnani, Ralph Thomas Boettcher, Markus Sperandio, Hans-Joachim Anders, Stefanie Steiger
Summary: This study investigates the impact of uric acid on neutrophils and finds that hyperuricemia impairs neutrophil function. Partial reduction of uric acid levels using uricase can partially restore the neutrophil defects. The study reveals that uric acid affects neutrophil migration by regulating intracellular pH and cytoskeletal dynamics. These findings have important implications for understanding immunodeficiency in kidney disease and sterile inflammation.
Article
Biochemistry & Molecular Biology
Irene Reimche, Haiqian Yu, Ni Putu Ariantari, Zhen Liu, Kay Merkens, Stella Rotfuss, Karin Peter, Ute Jungwirth, Nadine Bauer, Friedemann Kiefer, Joerg-Martin Neudoerfl, Hans-Guenther Schmalz, Peter Proksch, Nicole Teusch
Summary: The study shows that phenanthroindolizidine alkaloids (PAs) can effectively block nuclear factor kappa B (NF kappa B), thus having the potential to combat triple-negative breast cancer (TNBC). Additionally, PAs demonstrate better therapeutic effects against TNBC compared to the gold standard drug paclitaxel.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Reproductive Biology
Zhi Ma, Mirjana Kessler, Anca Chelariu-Raicu, Markus Sperandio, Sven Mahner, Udo Jeschke, Viktoria von Schoenfeldt
Summary: The expression of sLeX in the receptive endometrium is enhanced by IL-1 beta, facilitating trophoblast adhesion during embryo implantation. This study provides important insights into the molecular mechanisms of embryo implantation.
BIOLOGY OF REPRODUCTION
(2023)
Article
Biophysics
Nadine Bauer, Ivan Maisuls, Abel Pereira da Graca, Dirk Reinhardt, Raghu Erapaneedi, Nils Kirschnick, Michael Schafers, Carsten Grashoff, Katharina Landfester, Dietmar Vestweber, Cristian A. Strassert, Friedemann Kiefer
Summary: Hypoxia plays a crucial role in regulating cell metabolism, migration, and angiogenesis, and is involved in various pathological conditions. In this study, novel genetically-encoded reporters, dUnORS and dUnOFLS, were developed to accurately assess oxygen gradients in cells using ratiometric measurement and FRET-FLIM analysis. These reporters showed promising results in visualizing oxygen availability in vivo.
BIOSENSORS & BIOELECTRONICS
(2023)
Article
Biochemistry & Molecular Biology
Ivy K. N. Chiang, Matthew S. Graus, Nils Kirschnick, Tara Davidson, Winnie Luu, Richard Harwood, Keyi Jiang, Bitong Li, Yew Yan Wong, Mehdi Moustaqil, Emmanuelle Lesieur, Renae Skoczylas, Valerie Kouskoff, Jan Kazenwadel, Luis Arriola-Martinez, Emma Sierecki, Yann Gambin, Kari Alitalo, Friedmann Kiefer, Natasha L. Harvey, Mathias Francois
Summary: SOX7, a BEC-specific transcription factor, modulates the expression level of angiocrine signals in blood vascular endothelial cells (BECs) to pattern lymphatic vessels. It directly represses the transcription of Vegfc, a major lymphangiogenic growth factor, and interacts with HEY1 to regulate Notch pathway. Our finding reveals the importance of SOX7 in modulating downstream signaling events crucial for lymphatic patterning.
Article
Medicine, Research & Experimental
Ina Rohwedder, Lou Martha Wackerbarth, Kristina Heinig, Annamaria Ballweg, Johannes Altstaetter, Myriam Ripphahn, Claudia Nussbaum, Melanie Salvermoser, Susanne Bierschenk, Tobias Straub, Matthias Gunzer, Marc Schmidt-Supprian, Thomas Kolben, Christian Schulz, Averil Ma, Barbara Walzog, Matthias Heinig, Markus Sperandio
Summary: Newborns, especially premature infants, are prone to developing neonatal sepsis due to differences in immune system requirements during intrauterine and extrauterine life. Through transcriptomic analysis, we have identified the molecular mechanisms of neutrophil maturation and functional adaptation in fetal ontogeny. Our findings reveal constitutive activation of the noncanonical NF-KB pathway and upregulation of A20 in fetal neutrophils, leading to appropriate adaptation of neutrophil function during intrauterine fetal life but potentially hampering immune responses in prematurely born infants.
Article
Immunology
Aikaterini Gatsiou, Simon Tual-Chalot, Matteo Napoli, Almudena Ortega-Gomez, Tommy Regen, Rachit Badolia, Valeriana Cesarini, Claudia Garcia-Gonzalez, Raphael Chevre, Giorgia Ciliberti, Carlos Silvestre-Roig, Maurizio Martini, Jedrzej Hoffmann, Rana Hamouche, Joseph R. Visker, Nikolaos Diakos, Astrid Wietelmann, Domenico Alessandro Silvestris, Georgio Georgiopoulos, Ali Moshfegh, Andre Schneider, Wei Chan, Stefan Guenther, Johanne Backs, Shin Kwak, Craig H. Selzman, Kimon Stamatelopoulos, Stefan Rose-John, Christian Trautwein, Ioakim Spyridopoulos, Thomas Braun, Ari Waisman, Angela Gallo, Stavros G. Drakos, Stefanie Dimmeler, Markus Sperandio, Oliver Soehnlein, Konstantinos Stellos
Summary: RNA editor ADAR2 regulates endothelial responses to IL-6, controlling leukocyte trafficking in inflamed and ischemic tissues. ADAR2 is required for IL-6 trans-signaling and immune cell infiltration through suppressing primary microRNA processing.
Review
Medicine, General & Internal
Sebastian Sitaru, Agnes Budke, Riccardo Bertini, Markus Sperandio
Summary: Mounting experimental evidence suggests that the CXCL8-CXCR1/2 axis plays an essential role in neutrophils in the pathophysiology of inflammatory, autoimmune, and neoplastic diseases. Therapeutic targeting of CXCR1/2 or CXCL8 has been extensively studied using in vitro and animal disease models, showing potential benefits for patients with unwanted neutrophil-mediated inflammation. However, careful evaluation is needed for the use of inhibitors in severe infections or sepsis. Inhibition of the CXCL8-CXCR1/2 axis also holds promise for cancer therapy, with ongoing efforts to define its involvement in neoplastic diseases.
INTERNAL AND EMERGENCY MEDICINE
(2023)
Article
Allergy
Selina K. Jorch, Annika McNally, Philipp Berger, Jonas Wolf, Kim Kaiser, Andrian Chetrusca Covash, Stefanie Robeck, Isabell Pastau, Olesja Fehler, Saskia-L. Jauch-Speer, Sven Hermann, Michael Schafers, Hanne Van Gorp, Apurva Kanneganti, Joke Dehoorne, Filomeen Haerynck, Federica Penco, Marco Gattorno, Jae Jin Chae, Paul Kubes, Mohamed Lamkanfi, Andy Wullaert, Markus Sperandio, Thomas Vogl, Johannes Roth, Judith Austermann
Summary: This study provides evidence that S100A8/A9 alarmins are released through a pyrin/caspase-1/gasdermin D-dependent pathway in FMF patients, and they directly drive autoimmune inflammation in vivo.
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
(2023)
Review
Ophthalmology
Thomas Clahsen, Karina Hadrian, Maria Notara, Simona L. Schlereth, Antonia Howaldt, Verena Prokosch, Thomas Volatier, Deniz Hos, Falk Schroedl, Alexandra Kaser-Eichberger, Ludwig M. Heindl, Philipp Steven, Jacobus J. Bosch, Alexander Steinkasserer, Alexander C. Rokohl, Hanhan Liu, Mert Mestanoglu, Hamid Kashkar, Bjorn Schumacher, Friedemann Kiefer, Stefan Schulte-Merker, Mario Matthaei, Yanhong Hou, Sonja Fassbender, Jonathan Jantsch, Wei Zhang, Philip Enders, Bjorn Bachmann, Felix Bock, Claus Cursiefen
Summary: Traditionally, the eye was believed to lack lymphatic vessels. However, recent research has shown that lymphatic vessels have a role in various ocular pathologies. This review provides an overview of the pathogenetic role of ocular lymphatics and the potential therapeutic options based on molecular mechanisms. It discusses the role of lymphatic vessels in corneal angiogenesis, ocular surface pathologies, ocular tumors, and glaucoma, and emphasizes the importance of identifying molecular mechanisms and modulators of lymphangiogenesis for future treatments.
PROGRESS IN RETINAL AND EYE RESEARCH
(2023)
Article
Immunology
Monika Pruenster, Roland Immler, Jonas Roth, Tim Kuchler, Thomas Bromberger, Matteo Napoli, Katrin Nussbaumer, Ina Rohwedder, Lou Martha Wackerbarth, Chiara Piantoni, Konstantin Hennis, Diana Fink, Sebastian Kallabis, Tobias Schroll, Sergi Masgrau-Alsina, Agnes Budke, Wang Liu, Dietmar Vestweber, Christian Wahl-Schott, Johannes Roth, Felix Meissner, Markus Moser, Thomas Vogl, Veit Hornung, Petr Broz, Markus Sperandio
Summary: This study elucidates the mechanisms of S100A8/S100A9 release from neutrophils, revealing that E-selectin regulates the release of S100A8/S100A9 through NLRP3 and gasdermin D. This process serves as a rapid and reversible activation system that plays a crucial role in inflammation.
Article
Multidisciplinary Sciences
Won Ho Yang, Peter V. Aziz, Douglas M. Heithoff, Yeolhoe Kim, Jeong Yeon Ko, Jin Won Cho, Michael J. Mahan, Markus Sperandio, Jamey D. Marth
Summary: The colonic mucosal barrier provides protection against infection, inflammation, and tissue ulceration. The erosion of this barrier is a common feature of colitis, but the underlying molecular mechanisms are not well understood. This study used a food poisoning model to investigate the erosion of the mucosal barrier. The findings suggest that previous infection activates an innate immune mechanism that leads to the activation of Neu3 neuraminidase in colonic epithelial cells and increased secretion of Cathepsin-G protease by Paneth cells. These host responses, combined with the desialylation of Mucin-2, render the mucosal barrier susceptible to proteolytic breakdown. Inhibiting Cathepsin-G or Neu3 function can protect against proteolysis and barrier erosion, reducing the frequency and severity of colitis.