作者: Pawar, Atul Darasing ; Deka, Hemchandra ; Battula, Monishka Srinivas ; Patil, Pritee Chunarkar ; Abdelghani, Heba Taha M. ; Maiti, Surajit ; Chikhale, Rupesh V. ; Bhowmick, Shovonlal

Introduction:SYK (Spleen Tyrosine Kinase) regulates immune response and is a promising target for cancer, sepsis, and allergy therapies. This study aims to create novel compounds that serve as alternative inhibitors for cancer treatments targeting SYK.Method:A thorough combination of machine learning (ML) and physics-based methods was employed to achieve these goals, encompassing de novo design, multitier molecular docking, absolute binding affinity computation, and molecular dynamics (MD) simulation.Results:A total of 5576 novel molecules with key pharmacophoric features were generated using an ML-driven de novo approach against 21 diaminopyrimidine carboxamide analogs. Pharmacokinetic and toxicity evaluation assisted by the ML approach revealed that 4353 chemical entities fulfilled the acceptable pharmacokinetic and toxicity profiles. By screening through binding energy threshold from the physics-based multitier molecular docking, and ML-assisted absolute binding affinity identified the top four molecules such as RI809 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((2- aminocyclohexyl)oxy)benzamide), RI1393 (4-((2-aminocyclohexyl)amino)-2-(3-(1-methyl-1Hpyrazol- 5-yl)-4-(trifluoromethyl)benzyl)benzamide), RI2765 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((4- aminocyclohexyl)methyl)benzamide), and RI3543 (2-([1,1'-biphenyl]-2-ylmethyl)-4-(piperidin-3- yloxy)benzamide). The final molecules identified exhibit a strong affinity for SYK, attributed to their structural diversity and notable pharmacophoric characteristics. All-atom MD simulations showed that each final molecule retained significant binding interactions with SYK and stability in dynamic states, indicating their potential as anticancer agents. Calculated binding free energy for selected molecules using molecular mechanics with generalized Born and surface area (MMGBSA) ranged from -6 to -35 kcal/mol, indicating strong SYK affinity.Conclusion:In conclusion, the integration of AI and physics-based methods successfully developed promising SYK inhibitors with significant potential. The molecules reported could be vital anticancer agents subjected to experimental validation.

2025-01-07·Microbiology Spectrum

Spleen tyrosine kinase inhibitors disrupt human neutrophil swarming and antifungal functions

Article

作者: Viens, Adam L. ; Hopke, Alex ; Mansour, Michael K. ; Irimia, Daniel ; Alexander, Natalie J. ; Mun, Seok Joon

ABSTRACT Neutrophils communicate with one another and amplify their destructive power through swarming, a collective process that synchronizes the activities of multiple neutrophils against one target. The sequence of activities contributing to swarming against clusters of fungi has been recently uncovered. However, the molecular signals controlling the neutrophils’ activities during the swarming process are just emerging. Here, we report that spleen tyrosine kinase (SYK) inhibitors severely impair neutrophil swarming responses, resulting in the complete loss of fungal restriction. These findings are enabled by a microscale platform to probe the biology of human neutrophils swarming against uniformly sized clusters of growing Candida albicans , a representative opportunistic fungal pathogen. We take advantage of the ability to monitor large arrays of swarms and quantify the effect of multiple chemical inhibitors on different phases of human neutrophil swarming. We show that inhibitors that interfere with PI3Ky signaling disrupt the regulation of the initiation of swarming, while the activation of JNK signaling is essential for the activation of biochemical antifungal functions. Furthermore, we reveal that granulocyte colony-stimulating factors (GCSF and GM-CSF) can partially rescue the antifungal functions of neutrophils exposed to SYK inhibitors. These findings advance our understanding of neutrophil swarming biology in humans and lay the foundation for novel therapeutics that may restore neutrophil function during immunosuppression. IMPORTANCE Neutrophils can amplify their destructive power through swarming, a crucial process against large targets that individual neutrophils cannot destroy. However, the molecular mechanisms controlling this process are just emerging. Here, we leveraged microscale tools to probe the biology of swarming against fungi. We used multiple chemical inhibitors and mapped SYK, PI3Ky, and JNK signaling roles during human neutrophil swarming against fungal clusters of Candida albicans . We also found that treating human neutrophils with GCSF and GM-CSF rescues some neutrophil antifungal function during SYK inhibition. These findings advance our understanding of swarming biology in humans while laying the foundation for developing therapeutics that enhance neutrophil function during immunosuppression.

2025-01-06·Journal of Experimental Medicine

JNK1 inhibitors target distal B cell receptor signaling and overcome BTK-inhibitor resistance in CLL

Article

作者: Bräuer-Hartmann, Daniela ; Bauer, Marcus ; Chernyakov, Dmitry ; Follo, Marie ; Saleem, Shifa Khaja ; Dierks, Christine ; Skorobohatko, Oleksandra ; Schmidt, Cornelius ; Mathew, Nimitha ; Aumann, Konrad ; Decker, Sarah ; Wickenhauser, Claudia ; Herling, Marco ; Klein, Claudius ; Kissel, Sandra

Inhibition of the proximal B cell receptor (BCR) signaling pathway by BTK inhibitors is highly effective in the treatment of CLL, but drug resistance or intolerance occurs. Here, we investigated c-Jun N-terminal protein kinase 1 (JNK1) as an alternative drug target in the distal BCR pathway. JNK1 was preferentially overexpressed and activated in poor prognostic CLL with unmutated IGHV. Proximal BCR inhibition (BTK, PI3K, or SYK inhibitors) or SYK knockdown efficiently dephosphorylated JNK1, identifying JNK1 as a critical BCR downstream kinase in CLL. JNK1 inhibition induced apoptosis in primary CLL cells, resulting in the downregulation of BCL2, MCL1, and c-JUN. JNK1 inhibition in patient-derived CLL xenografted mice and Eµ-TCL1-tg mice prevented CLL progression, reduced splenic infiltration, and restored T cell function and normal hematopoiesis. JNK1 inhibitors even remained effective in ibrutinib refractory CLL. In conclusion, our study revealed JNK1 as a promising drug target in CLL downstream of the BCR, overcoming ibrutinib resistance, blocking the protective microenvironment, and improving CLL-specific immunosuppressive mechanisms.

项与 SYK inhibitors (Origenis) 相关的新闻（医药）

2023-12-28

·SYNAPSE

What are Syk inhibitors and how do you quickly get the latest development progress?

Syk (Spleen Tyrosine Kinase) is a crucial enzyme found in the human body that plays a significant role in immune cell signaling. It is primarily expressed in cells of the hematopoietic system, such as B cells, T cells, and mast cells. Syk acts as a key mediator in various immune responses, including B cell receptor signaling, Fc receptor signaling, and integrin signaling. By initiating downstream signaling cascades, Syk regulates immune cell activation, differentiation, and cytokine production. Due to its pivotal role in immune cell function, Syk has emerged as a potential therapeutic target for various immune-related disorders, including autoimmune diseases and certain cancers. The analysis of the current competitive landscape and future development of target Syk reveals that Rigel Pharmaceuticals, Inc., Novartis AG, HUTCHMED (China) Ltd., and TopiVert Ltd. are among the companies growing fastest under this target. These companies have made significant progress in the R&D of drugs targeting Syk, with drugs in the Approved and Phase 3 stages. Drugs targeting Syk have been approved for various indications, covering a wide range of diseases and conditions. Small molecule drugs are progressing most rapidly, indicating their potential as therapeutic options. The development of drugs targeting Syk is taking place in various countries/locations, with the United States, European Union, and China being prominent players. Further research and development are needed to fully explore the potential of drugs targeting Syk and address the inactive drugs in the pipeline. How do they work?Syk inhibitors are a type of medication that target and inhibit the activity of the spleen tyrosine kinase (Syk) enzyme. From a biomedical perspective, Syk is an enzyme involved in signaling pathways within immune cells, particularly B cells and mast cells. It plays a crucial role in the activation of these cells and the release of inflammatory mediators. Syk inhibitors work by binding to the Syk enzyme and blocking its activity. By inhibiting Syk, these medications can help regulate immune responses and reduce inflammation. They are primarily used in the treatment of certain autoimmune diseases, such as rheumatoid arthritis and immune thrombocytopenic purpura. These inhibitors are considered targeted therapies as they specifically target the Syk enzyme, minimizing potential side effects on other cellular processes. They can be administered orally or intravenously, depending on the specific medication. Syk inhibitors have shown promising results in clinical trials and are an active area of research in the field of biomedicine. List of Syk InhibitorsThe currently marketed Syk inhibitors include: Fostamatinib DisodiumMidostaurinSovleplenibIMG-016TOP-1630CerdulatinibEntospletinib DimesylateGusacitinibIC-265IC-270For more information, please click on the image below. What are Syk inhibitors used for?Syk inhibitors are primarily used in the treatment of certain autoimmune diseases, such as rheumatoid arthritis and immune thrombocytopenic purpura. For more information, please click on the image below to log in and search. How to obtain the latest development progress of Syk inhibitors?In the Synapse database, you can keep abreast of the latest research and development advances of Syk inhibitors anywhere and anytime, daily or weekly, through the "Set Alert" function. Click on the image below to embark on a brand new journey of drug discovery!

100 项与 SYK inhibitors (Origenis) 相关的药物交易

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