2. Academic Validation
  3. Interleukin-1β converting enzyme (ICE): A comprehensive review on discovery and development of caspase-1 inhibitors

Interleukin-1β converting enzyme (ICE): A comprehensive review on discovery and development of caspase-1 inhibitors

  • Eur J Med Chem. 2023 Dec 5:261:115861. doi: 10.1016/j.ejmech.2023.115861.
Palmi Modi 1,  Bhumi M Shah 1,  Shivani Patel 2
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, L. J. Institute of Pharmacy, L J University Ahmedabad - 382 210, Gujarat, India.
  • 2 Division of Biological and Life Sciences, Ahmedabad University, Ahmedabad, 380009, Gujarat, India. Electronic address: [email protected].
PMID: 37857145 DOI: 10.1016/j.ejmech.2023.115861
Abstract

Caspase-1 is a critical mediator of the inflammatory process by activating various pro-inflammatory cytokines such as pro-IL-1β, IL-18 and IL-33. Uncontrolled activation of Caspase-1 leads to various cytokines-mediated diseases. Thus, inhibition of Caspase-1 is considered therapeutically beneficial to halt the progression of such diseases. Currently, rilonacept, canakinumab and anakinra are in use for caspase-1-mediated autoinflammatory diseases. However, the poor pharmacokinetic profile of these peptides limits their use as therapeutic agents. Therefore, several peptidomimetic inhibitors have been developed, but only a few compounds (VX-740, VX-765) have advanced to clinical trials; because of their toxic profile. Several small molecule inhibitors have also been progressing based on the three-dimensional structure of Caspase-1. However there is no successful candidate available clinically. In this perspective, we highlight the mechanism of Caspase-1 activation, its therapeutic potential as a disease target and potential therapeutic strategies targeting Caspase-1 with their limitations.

Keywords

Autoinflammatory diseases; Caspase-1; Cytokines; Peptidomimetics.

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