Cysteine-aspartic protease (Caspase) (CASP)

Caspases are a family of highly conserved cysteine proteases that serve as the primary executioners of programmed cell death (apoptosis) and essential mediators of the innate immune inflammatory response [10, 11]. They are synthesized as inactive pro-enzymes (procaspases) that undergo proteolytic activation in response to specific apoptotic triggers or inflammatory complexes such as the inflammasome [1, 8, 13]. Functionally, the family is categorized into initiator caspases (e.g., Caspases 8 and 9), which trigger signaling cascades, and effector caspases (e.g., Caspases 3 and 7), which carry out the final dismantling of cellular components [9, 11]. Additionally, inflammatory caspases like Caspase-1 facilitate the maturation of pro-inflammatory cytokines such as IL-1β and IL-18 and induce a lytic form of cell death known as pyroptosis [11, 14]. In the context of pharmacology, caspases are major therapeutic targets across several disease domains [2, 3]. In oncology, drug development focuses on activating caspases to restore apoptotic pathways in resistant tumor cells [1, 9]. Conversely, in neurodegenerative and inflammatory diseases, small-molecule inhibitors are employed to prevent excessive cell loss and cytokine-driven tissue damage [3, 4, 11]. However, therapeutic targeting is complicated by the risk of triggering alternative, non-regulated cell death pathways like necrosis when apoptosis is inhibited [15, 16].

Other names

Cysteine-aspartic proteasesCysteine aspartasesCysteine-dependent aspartate-directed proteasesInterleukin-1 beta converting enzyme familyICE familyCASP

Drugs targeting this family typically function through either the direct inhibition of the active site cysteine to prevent substrate cleavage or the allosteric activation of procaspases to induce tumor cell death.