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.

Fig. 1. Structural and functional characteristics of caspases.

The members of the caspase family are grouped based on their functional contribution in inflammation (caspases-1, -4, -5, and -11) and involvement in cell death (initiation: caspases-2, -8, -9, and -10; execution: caspases-3, -6, and -7) or by their consensus recognition sequences. Inflammatory caspases recognize the sequence Trp-Glu-His-Asp and are classified as group I. Whilst group II and group III recognize Asp-Glu-X-Asp and (Leu/Val)-Glu-X-Asp, respectively. Although caspase-12 and -14 are classified as group I, these caspases do not share the same functional role as inflammatory group I caspases. Instead, caspase-12 is believed to be a negative regulator of caspase-1 and to promote ER stress-induced apoptosis in rodents; and caspase-14 in epidermal formation. Structurally, inflammatory and initiator apoptotic caspases have a long pro-domain with a CARD or DED domain component which facilitates its recognition by a multiprotein complex or adapter molecule on death receptors, respectively, for its activation. Unlike initiator apoptotic caspases, executioner caspases lack a CARD or DED domain and require proteolytic cleavage of the inter-subunit linker for its dimerization and activation. Apart from the conventional functions of caspases, alternate roles including differentiation, migration and development in various cell types have added to their functions and have revealed the possible crosstalk between caspases and other molecular pathways. However, these roles are not yet well defined. X: represents an amino acid.