التفاصيل البيبلوغرافية
| العنوان: |
Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors |
| المؤلفون: |
Li Liu (75607), Manshu Tang (2171179), Rajan Pragani (105058), Frank G. Whitby (3590531), Ya-qin Zhang (11403266), Bijina Balakrishnan (11403269), Yuhong Fang (3032253), Surendra Karavadhi (6051887), Dingyin Tao (488326), Christopher A. LeClair (2201161), Matthew D. Hall (316516), Juan J. Marugan (191299), Matthew Boxer (105062), Min Shen (68726), Christopher P. Hill (338170), Kent Lai (2171176), Samarjit Patnaik (1878463) |
| سنة النشر: |
2021 |
| المجموعة: |
Smithsonian Institution: Digital Repository |
| مصطلحات موضوعية: |
Biochemistry, Medicine, Molecular Biology, Pharmacology, Biotechnology, Cancer, Infectious Diseases, Plant Biology, Chemical Sciences not elsewhere classified, previous work identified, potent biochemical inhibition, pharmacokinetic properties suitable, low micromolar concentrations, chronic complications associated, yielded novel analogs, 100 nm ), treating classic galactosemia, rare disease caused, 50 , 1 phosphate uridylyltransferase, 1 phosphate, novel strategy, galt ), rodent models, optimization campaign, major cause, lead compounds, inhibiting galactokinase, inherited deficiency, derived cells |
| الوصف: |
Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure–activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC 50 < 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia. |
| نوع الوثيقة: |
article in journal/newspaper |
| اللغة: |
unknown |
| Relation: |
https://figshare.com/articles/journal_contribution/Structure-Based_Optimization_of_Small_Molecule_Human_Galactokinase_Inhibitors/16583588 |
| DOI: |
10.1021/acs.jmedchem.1c00945.s001 |
| الاتاحة: |
https://doi.org/10.1021/acs.jmedchem.1c00945.s001 |
| Rights: |
CC BY-NC 4.0 |
| رقم الانضمام: |
edsbas.7D010231 |
| قاعدة البيانات: |
BASE |