Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.bmcl.2019.126680 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Preliminary Evidence for Perturbation-Based tACS-EEG Biomarkers of Gamma Activity in Alzheimer's Disease.
Int J Geriatr Psychiatry
January 2025
Precision Neuroscience & Neuromodulation Program, Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Background: Alzheimer's disease (AD) is characterized by impaired inhibitory circuitry and GABAergic dysfunction, which is associated with reduced fast brain oscillations in the gamma band (γ, 30-90 Hz) in several animal models. Investigating such activity in human patients could lead to the identification of novel biomarkers of diagnostic and prognostic value. The current study aimed to test a multimodal "Perturbation-based" transcranial Alternating Current Stimulation-Electroencephalography (tACS)-EEG protocol to detect how responses to tACS in AD patients correlate with patients' clinical phenotype.
View Article and Find Full Text PDFClinician perspectives on designing and implementing a hereditary cancer transition clinic.
Hered Cancer Clin Pract
January 2025
Department of Population Health Sciences, Geisinger, Danville, PA, 17822, USA.
Article Synopsis
- Early identification of hereditary cancer predisposition in adolescents and young adults is crucial for targeted cancer prevention and improving survival rates, but this age group faces unique healthcare transition challenges.
- The study aimed to gather expert insights on creating a transition clinic for this demographic, using qualitative methods inspired by human-centered design and implementation science.
- Key findings emphasized the importance of relationship building, care coordination, education, effective communication among providers, and establishing a sustainable clinic model to enhance program implementation.
Development of a mitochondrial mini-barcode and its application in metabarcoding for identification of leech in traditional Chinese medicine.
Sci Rep
January 2025
National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry, State Institute of Pharmaceutical Industry, 201203, Shanghai, People's Republic of China.
In Traditional Chinese Medicine (TCM), the medicinal leech is vital for treatments to promote blood circulation and eliminate blood stasis. However, the prevalence of counterfeit leech products in the market undermines the quality and efficacy of these remedies. Traditional DNA barcoding techniques, such as the COI barcode, have been limited in their application due to amplification challenges.
View Article and Find Full Text PDFDiagnostic Accuracy of Imperforate Hymen at a Single Referral Center.
J Pediatr Adolesc Gynecol
January 2025
Division of Pediatric and Adolescent Gynecology, Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas.
Study Objective: Imperforate hymen (IH) is a rare congenital anomaly that results in vaginal outlet obstruction. IH can cause significant morbidity if not managed appropriately, which depends on accurate identification of the condition. However, data on the accuracy of IH diagnosis is limited.
View Article and Find Full Text PDFTetrabromobisphenol A, but not bisphenol A, disrupts plasma membrane homeostasis in myeloid cell models - A novel threat from an established persistent organic pollutant.
Sci Total Environ
January 2025
Department of Oncobiology and Epigenetics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, Poland; Laboratory of Transcriptional Regulation, Institute of Medical Biology PAS, Lodz, Poland. Electronic address:
Article Synopsis
- The study investigates the effects of Bisphenol A (BPA) and Tetrabromobisphenol A (TBBPA) on the dynamics of biological membranes, focusing on how these persistent organic pollutants impact myeloid cell lines.
- It was found that TBBPA specifically disrupts the plasma membrane's biophysical homeostasis, increasing mobility and decreasing order, while BPA showed no significant effects.
- The findings highlight TBBPA's potential to impair immune function, emphasizing the environmental toxicity concerns associated with persistent organic pollutants.
Want AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!