Caspase Inhibitors: A Pharmaceutical Industry Perspective

Abstract

Caspase inhibition has been demonstrated to be therapeutically effective in moderating excessive programmed cell death, or apoptosis. Publications detailing programs in the pharmaceutical industry have been more frequent in recent years, ranging from SAR studies to clinically relevant animal models of disease. A summary of the work published in this exciting new area is presented, outlining the broad applicability of this fundamental cellular mechanism across several disease indications. This area of research has matured to the level of advancing compounds into clinical trials: VX-740 (Pralnacasan) and VX-765 as anti-inflammatory agents, and IDN-6556, a pan-caspase inhibitor as an anti-apoptotic agent.

Molecules that modulate Apaf‐1 activity

“…Putative drug targets derived from cell death studies have permitted the advancement through different clinical phases of pharmacological candidates. 23 In fact, most of the key players in the apoptotic signaling pathway have been explored as drug targets: death receptors that control apoptosis induction from the cell surface, 178 caspases that are the executioners of apoptosis, 26,27 endogenous caspase inhibitors as IAP, 179 and Bcl-2 protein family members. 120 However, the apoptosome and its primary scaffolding protein Apaf-1, have been less tractable as drug targets.…”

“…7,23,24 To identify molecules that could ameliorate disease-associated excessive apoptosis, drug discovery efforts initially targeted the inhibition of caspase activity, particularly the effector caspase-3. [25][26][27][28] However, caspase-3 inhibitors have encountered problems in their pharmacological development. The active sites of all caspases have a requirement for an aspartyl functionality in the P1 amino acid and an electrophilic carbonyl, necessary to engage the catalytic cysteine.…”

Unnatural amino acids increase sensitivity and provide for the design of highly selective caspase substrates

“…The apoptotic process is somewhat hierarchical and caspases can be assigned as initiators (2,8,9, and 10) and executioners (3,6, and 7). [1][2][3] Apoptosis can be triggered extrinsically via ligation of a death receptor by its cognate ligands, leading to the activation of caspases 8 and 10, or intrinsically following the release of cytochrome c from mitochondria with formation of a caspase 9 activation complex known as the apoptosome.…”

“…2,[8][9][10][11] Unfortunately, most of them lack selectivity and cannot be used for selectively targeting or analyzing particular enzymes in complex biological environments. [12][13][14][15] This is entirely because of the overlapping specificities of the caspases on their preferred natural amino acid sequences.…”

Autophagic cell death unraveled: Pharmacological inhibition of apoptosis and autophagy enables necrosis

“…A commonly utilized apoptosis inhibitor, zVAD, which blocks caspase protease activity required for apoptosis, is reported to induce autophagic cell death in some circumstances. 2 Since excessive apoptosis is associated with some degenerative conditions, caspase inhibitors are thought to be of therapeutic value, 9 but not so if they instead promote autophagic cell death. Wu and colleagues 1 shed some light on this issue with their observation that zVAD inhibits caspases but also the lysosomal protease Cathepsin B.…”