2026-07-01 | In Silico Drug Repositioning Identifies SYK Kinase Inhibitors as Potential Neuroprotective Agents for Ataxia-Telangiectasia.
Ataxia-Telangiectasia (AT) is a rare neurodegenerative disorder characterized by progressive neuronal loss and chronic neuroinflammation. Emerging evidence indicates that aberrant overexpression of the adaptor protein TYROBP promotes sustained recruitment and activation of spleen tyrosine kinase (SYK), contributing to pathogenic inflammatory signaling in AT. In this study, we applied a drug repositioning strategy to identify clinically approved compounds that inhibit SYK activity. An integrated in silico workflow was employed, combining convolutional neural network (CNN)-based molecular docking with network medicine analysis using the SAveRUNNER platform to screen a library of 2342 FDA-approved drugs. The top-ranked candidates were further evaluated using long-timescale molecular dynamics simulations and post-simulation redocking to assess their binding stability and conformational persistence within the SYK catalytic pocket under explicit solvent conditions. This multilevel computational analysis identified vemurafenib and palbociclib as the most promising SYK inhibitors, both exhibiting sustained binding affinity and stable intermolecular interactions following protein relaxation. These findings support the feasibility of repurposing FDA-approved drugs to modulate SYK-driven neuroinflammatory pathways and provide a mechanistic framework for developing novel neuroprotective interventions for AT.
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2026-06-26 | Common DNA Damage Response Factors Required for Cellular Resistance to Inhibitors for the Ataxia Telangiectasia and Rad3-Related Checkpoint Kinase in Hematopoietic Cells.
Targeting checkpoints is one of the most promising strategies in cancer chemotherapy. Leukemia, in particular, is expected to yield high therapeutic efficacy due to its high replication stress. However, the DNA damage response factors involved in the vulnerability to checkpoint inhibitors of these hematopoietic cancers remain elusive. In this study, we reveal common factors required for cellular resistance to ATR inhibition in hematopoietic cancer cells. We explored the DNA damage response pathways contributing to cellular tolerance to three types of ATR inhibitors using an isogenic DNA repair factor mutant collection derived from the chicken lymphoma cell line, DT40. We first demonstrated significant ATR inhibition activity of the recently developed Torin2 analogous compounds, SPK67 and SPK98, under stressed replication conditions. We then compared cellular sensitivity patterns of the known ATR inhibitor, VE-821, and the potential ATR inhibitors, SPK67 and SPK98, in 24 types of mutants deficient in genome maintenance systems and found that RAD17/-, FEN1-/-, and POLB-/- cells exhibited hypersensitivity to all these drugs. Consistently, these mutant cells exhibited increased chromosome instability upon treatment with VE-821, SPK67, and SPK98, resulting in apoptosis. These results suggest that Rad17, Fen1, and Polymerase β play roles in responding to DNA damage caused by these drugs. However, ATR inhibition did not result in cell-cycle arrest, Chk1 phosphorylation, or increased γH2AX levels. These results suggest that, although ATR inhibition causes DNA damage, impaired checkpoint function suppresses the appropriate activation of DNA damage signaling pathways, thereby leading to cell death. This study is the first to demonstrate the importance of Rad17, Fen1, and Polymerase β in cellular tolerance to ATR inhibition in hematopoietic cells.
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2026-06-23 | Transcriptional Profiling Shows Dampening of Interferon Gene Signatures by NAD+ Augmentation in Ataxia-Telangiectasia
Ataxia-Telangiectasia (A-T) is a multisystem disorder caused by loss of A-T mutated (ATM) protein activity, characterized clinically by immunodeficiency and cerebellar ataxia. ATM is a master regulator of DNA damage responses and loss of ATM function is accompanied by persistent activation of PARP1 leading to depletion of intracellular NAD+ and dysfunction of a series of cellular signalling pathways dependent on NAD+, providing a mechanistic rationale for NAD+ augmentation therapy. We performed a clinical trial of NAD+ augmentation with nicotinamide riboside (NR) over 24 months in A-T patients where we observed improved coordination and eye movements in A-T patients. Here, by using peripheral blood mononuclear cells, we performed longitudinal transcriptome profiling to define molecular signatures of A-T and to assess pathway-level responses to NR supplementation. A-T patients exhibited reproducible transcriptomic alterations involving immune, vascular, and inflammatory pathways. NAD+ augmentation was associated with suppression of interferon response genes and modulation of networks correlated with neurological improvement. These findings establish systemic molecular signatures of A-T and identify potential blood-based biomarkers that reflect disease processes and therapeutic response, supporting the use of NAD+ augmentation as a disease-modifying strategy in A-T by dampening interferon signalling.
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