Cuellar, Matthew E. and Yang, Mu and Karavadhi, Surendra and Zhang, Ya-Qin and Zhu, Hu and Sun, Hongmao and Shen, Min and Hall, Matthew D. and Patnaik, Samarjit and Ashe, Karen H. and Walters, Michael A. and Pockes, Steffen (2023) An electrophilic fragment screening for the development of small molecules targeting caspase-2. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 259: 115632. ISSN 0223-5234, 1768-3254
Full text not available from this repository. (Request a copy)Abstract
Recent Alzheimer's research has shown increasing interest in the caspase-2 (Casp2) enzyme. However, the available Casp2 inhibitors, which have been pentapeptides or peptidomimetics, face challenges for use as CNS drugs. In this study, we successfully screened a 1920-compound chloroacetamide-based, electrophilic fragment library from Enamine. Our two-point dose screen identified 64 Casp2 hits, which were further evaluated in a ten-point dose-response study to assess selectivity over Casp3. We discovered compounds with inhibition values in the single-digit micromolar and sub-micromolar range, as well as up to 32-fold selectivity for Casp2 over Casp3. Target engagement analysis confirmed the covalent-irreversible binding of the selected fragments to Cys320 at the active site of Casp2. Overall, our findings lay a strong foundation for the future development of small-molecule Casp2 inhibitors.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CYSTEINE PROTEASE; NEDD2 GENE; DISCOVERY; TAU; INHIBITORS; SITE; CLEAVAGE; ENCODES; DEATH; MODEL; |
| Subjects: | 500 Science > 540 Chemistry & allied sciences |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 30 Jan 2024 13:24 |
| Last Modified: | 30 Jan 2024 13:24 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60369 |
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