Molecular Classification
Enzyme (specifically, cysteine-aspartic acid protease), Peptidase C14A family (caspases)
Other Names
CASP3, CPP32, CPP32B, SCA-1, Apopain, Yama, Cysteine protease CPP32
Disease Roles
Cancer (dysregulation can lead to resistance to cell death or excessive cell loss)Neurodegenerative disease (notably Alzheimer’s disease via amyloid precursor protein cleavage)Ischemia/reperfusion injury

Caspase-3, apoptosis-related cysteine peptidase Overview

Caspase‐3 is a key executioner enzyme within the cysteine-aspartic acid proteases (“caspases”) family that orchestrates programmed cell death (“apoptosis”). It exists as an inactive proenzyme (“procaspase‐3”) which becomes activated through proteolytic cleavage by initiator caspases such as caspases‐8, ‑9, or ‑10. Once active, it catalyzes the selective cleavage of numerous cellular substrates—including poly(ADP-ribose) polymerase (PARP), sterol regulatory element binding proteins (SREBPs), amyloid precursor protein—and activates downstream effector caspases like caspases 6 and 7. This central role makes it essential not only for normal development but also highly relevant in pathologies where apoptosis is dysregulated such as cancer resistance mechanisms or neurodegeneration due to inappropriate neuronal loss. Its activity can be measured using specific antibodies against its cleaved form—a gold-standard marker for cells undergoing apoptosis.

Mechanism of Action

Drugs targeting Caspase‑3 typically act by one of the following mechanisms: - Direct inhibition of enzymatic activity via covalent or non-covalent binding to the active site cysteine residue. - Activation by promoting zymogen processing or mimicking upstream apoptotic signals. - Indirect modulation through upstream pathway regulation affecting initiator caspases.

Biological Functions

Apoptosis (execution-phase effector)
Proteolytic cleavage of cellular proteins during cell death
Cleavage and activation/inactivation of other caspases and regulatory proteins (e.g., PARP, SREBPs)

Disease Associations

Cancer (dysregulation can lead to resistance to cell death or excessive cell loss)
Neurodegenerative disease (notably Alzheimer’s disease via amyloid precursor protein cleavage)
Ischemia/reperfusion injury

Safety Considerations

  • Notable safety concerns include potential for excessive tissue damage if broadly activated systemically, leading to unwanted cell death in healthy tissues. Inhibition may impair normal apoptotic processes required for tissue homeostasis or immune function. Therapeutic modulation requires careful targeting to avoid toxicity.

Interacting Drugs

PAC‑1 (activator)
Z-DEVD-FMK and Ac-DEVD-CMK (inhibitors; research use)
Emricasan/IDN‑6556 (pan-caspase inhibitor; clinical trials for liver diseases)
VX‑765/VX‑740/Pralnacasan/CVX0071307/Belnacasan* (*primarily caspase‑1 inhibitors but may have off-target effects on executioner caspases like Caspase‑3 in some contexts)

Associated Biomarkers

Biomarker
Caspase‑3 activation—especially detection of cleaved Caspase‑3—is widely used as a biomarker for apoptosis induction in both research and clinical settings. Antibodies against cleaved Caspase‐3 are standard tools for monitoring efficacy in preclinical drug development