An electrophilic fragment screening for the development of small molecules targeting caspase-2

Matthew E. Cuellar, Mu Yang, Surendra Karavadhi, Ya Qin Zhang, Hu Zhu, Hongmao Sun, Min Shen, Matthew D. Hall, Samarjit Patnaik, Karen H. Ashe, Michael A. Walters, Steffen Pockes

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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.

Original languageEnglish (US)
Article number115632
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Nov 5 2023

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© 2023 Elsevier Masson SAS

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