A long way to go: caspase inhibitors in clinical use

Abstract

Caspases are an evolutionary conserved family of cysteine-dependent proteases that are involved in many vital cellular processes including apoptosis, proliferation, differentiation and inflammatory response. Dysregulation of caspase-mediated apoptosis and inflammation has been linked to the pathogenesis of various diseases such as inflammatory diseases, neurological disorders, metabolic diseases, and cancer. Multiple caspase inhibitors have been designed and synthesized as a potential therapeutic tool for the treatment of cell death-related pathologies. However, only a few have progressed to clinical trials because of the consistent challenges faced amongst the different types of caspase inhibitors used for the treatment of the various pathologies, namely an inadequate efficacy, poor target specificity, or adverse side effects. Importantly, a large proportion of this failure lies in the lack of understanding various caspase functions. To overcome the current challenges, further studies on understanding caspase function in a disease model is a fundamental requirement to effectively develop their inhibitors as a treatment for the different pathologies. Therefore, the present review focuses on the descriptive properties and characteristics of caspase inhibitors known to date, and their therapeutic application in animal and clinical studies. In addition, a brief discussion on the achievements, and current challenges faced, are presented in support to providing more perspectives for further development of successful therapeutic caspase inhibitors for various diseases.

The NLRP1 Inflammasome Induces Pyroptosis in Human Corneal Epithelial Cells

“… 49 Moreover, caspase-1 inhibitors have thus far been limited by poor specificity and lack of efficacy with none yet advancing past phase II clinical trials. 50 , 51 Nevertheless, we speculate other proteins that modulate the NLRP1 pathway are yet to be discovered, and that these proteins, or even potentially NLRP1 itself, may ultimately become targets for drugs to treat these inflammasomopathies.…”

Ablation of GSDMD Attenuates Neurological Deficits and Neuropathological Alterations After Traumatic Brain Injury

“…In addition, other researchers aimed to develop caspase 1 inhibitors for the attenuation of inflammasome activation. Although the role of caspase 1 in cell death and inflammation have been demonstrated, emerging researches showed alternative caspase-independent pathway activated when performing caspase inhibition, which resulted in inadequate efficacy (Dhani et al, 2021 ); and the poor target specificity also limits the clinical application of caspase inhibitors (Kesavardhana et al, 2020 ). GSDMD was newly found as a pyroptosis executor and serves as a potent target for pyroptosis related diseases (Shi et al, 2015 ); and it is found that disulfiram, a drug used to treat alcohol addiction, could inhibit pyroptosis by blocking GSDMD pore formation (Hu et al, 2020 ).…”

Caspase Inhibition as a Possible Therapeutic Strategy for Pemphigus Vulgaris: A Systematic Review of Current Evidence

“…Given that current literature regarding the role of caspases in PV demonstrates that caspase inhibition may reduce acantholysis in PV, further well-designed studies are required to confirm this relationship. Additionally, there are no caspase inhibitor medications clinically approved for use [ 35 ]. Thus, if caspase inhibitors are to be considered in future therapeutic treatment of PV, safety concerns and side effects in humans would need to be thoroughly evaluated.…”