Cuellar ME, Yang M, Karavadhi S, Zhang YQ, Zhu H, Sun H, Shen M, Hall MD, Patnaik S, Ashe KH, Walters MA, Pockes S. An Electrophilic Fragment Screening for the Development of Small Molecules Targeting Caspase-2. European Journal of Medicinal Chemistry. 2023;259:115632. PMID: 37541771. DOI: 10.1016/j.ejmech.2023.115632.
Summary
This study advanced caspase-2 inhibitor discovery beyond peptide-like scaffolds by screening an electrophilic chloroacetamide fragment library. A 1,920-compound screen identified 64 initial caspase-2 hits, which were further evaluated for potency and selectivity against caspase-3. Selected fragments showed micromolar to submicromolar activity and up to 32-fold selectivity. Target engagement studies confirmed covalent binding to the active-site cysteine, providing a foundation for the development of smaller, more drug-like caspase-2 inhibitors.
Key Findings
- A 1,920-compound electrophilic fragment library was screened.
- Sixty-four caspase-2 hits were identified.
- Selected fragments showed up to 32-fold selectivity over caspase-3.
- Covalent engagement of the caspase-2 active-site cysteine was confirmed.
Impact on the Caspase-2/Tau Program
This paper paved the way for non-peptidic, CNS-oriented caspase-2 inhibitors. It provided fragment starting points for optimization into more drug-like therapeutic candidates.