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Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR.
Nat Commun
November 2024
Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
Lesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing.
View Article and Find Full Text PDFDiscovery of dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitors using an artificial intelligence model and their effects on tau and tubulin dynamics.
Biomed Pharmacother
December 2024
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan; TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan; Cancer Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. Electronic address:
The dual-specificity tyrosine-phosphorylation-regulated kinase 1 A (DYRK1A) presents a promising therapeutic target for neurological diseases. However, current inhibitors lack selectivity, which can lead to unexpected side effects and increase the difficulty of studying DYRK1A. Therefore, identifying selective inhibitors targeting DYRK1A is essential for reducing side effects and facilitating neurological disease research.
View Article and Find Full Text PDFDevelopment and Evaluation of ABI-171, a New Fluoro-Catechin Derivative, for the Treatment of Idiopathic Pulmonary Fibrosis.
Int J Mol Sci
November 2024
Center for Interstitial Lung Diseases, University of Washington Medical Center, Seattle, WA 98195, USA.
Article Synopsis
- Researchers developed a new small molecule, ABI-171, targeting specific kinases related to idiopathic pulmonary fibrosis (IPF) to combat its progression and high mortality rates.
- In a mouse model, ABI-171 showed significant improvements in lung health, reducing fibrosis and inflammation, as well as weight loss in treated mice, whether given before or after disease onset.
- The treatment led to lower mortality rates and better overall lung function compared to current treatments like pirfenidone and EGCG, indicating ABI-171's potential as a promising therapy for IPF.
Discovering a novel dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) inhibitor and its impact on tau phosphorylation and amyloid-β formation.
J Enzyme Inhib Med Chem
December 2024
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
Dual-specificity tyrosine-regulated kinase 1 A (DYRK1A) is crucial in neurogenesis, synaptogenesis, and neuronal functions. Its dysregulation is linked to neurodegenerative disorders like Down syndrome and Alzheimer's disease. Although the development of DYRK1A inhibitors has significantly advanced in recent years, the selectivity of these drugs remains a critical challenge, potentially impeding further progress.
View Article and Find Full Text PDFDiscovery and Functional Characterization of a Potent, Selective, and Metabolically Stable PROTAC of the Protein Kinases DYRK1A and DYRK1B.
J Med Chem
October 2024
Division of Drug Discovery and Development, Department of Pharmacology and Toxicology, College of Pharmacy The University of Arizona, Tucson, Arizona 85721, United States.
Small-molecule-induced protein degradation has emerged as a promising pharmacological modality for inactivating disease-relevant protein kinases. DYRK1A and DYRK1B are closely related protein kinases that are involved in pathological processes such as neurodegeneration, cancer development, and adaptive immune homeostasis. Herein, we report the development of the first DYRK1 proteolysis targeting chimeras (PROTACs) that combine a new ATP-competitive DYRK1 inhibitor with ligands for the E3 ubiquitin ligase component cereblon (CRBN) to induce ubiquitination and subsequent proteasomal degradation of DYRK1A and DYRK1B.
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