Abstract
Recombinant soluble TRAIL and agonistic antibodies against TRAIL receptors (DR4 and DR5) are currently being created for clinical cancer therapy, due to their selective killing of cancer cells and high safety characteristics. However, resistance to TRAIL and other targeted therapies is an important issue facing current cancer research field. An attractive strategy to sensitize resistant malignancies to TRAIL-induced cell death is the design of small molecules that target and promote caspase 8 activation. For the first time, we describe the discovery and characterization of a small molecule that directly binds caspase 8 and enhances its activation when combined with TRAIL, but not alone. The molecule was identified through an in silico chemical screen for compounds with affinity for the caspase 8 homodimer’s interface. The compound was experimentally validated to directly bind caspase 8, and to promote caspase 8 activation and cell death in single living cells or population of cells, upon TRAIL stimulation. Our approach is a proof-of-concept strategy leading to the discovery of a novel small molecule that not only stimulates TRAIL-induced apoptosis in cancer cells, but may also provide insights into the structure-function relationship of caspase 8 homodimers as putative targets in cancer.
Highlights
Apoptotic cell death is a mean to eliminate unwanted or damaged cells[1,2,3]
We designed an in silico screening to identify for the first time small molecules that bind caspase 8 and stabilize the zymogen caspase 8 homodimerization, resulting in a productive caspase 8 conformation that initiates faster processing of mature caspase 8
We targeted the zymogen caspase 8 interface region formed by the small subunit: by first generating a model of the zymogen caspase 8 structure based on the X-ray structure of zymogen caspase 8 in complex with cFLIPL (PDB ID: 3H13) and using it for in silico molecular docking studies
Summary
Apoptotic cell death is a mean to eliminate unwanted or damaged cells[1,2,3]. Caspase 8 is a cysteine protease that initiates a cell death response mediated by a group of receptors of the tumor necrosis factor (TNF) superfamily, including TRAIL, commonly known as death receptors[1,4]. The apoptosis process is triggered by recruitment of adaptor proteins, such as FAS-associated death domain (FADD), to the death receptors, which is followed by recruitment of caspase 8 pro-enzyme This causes dimerization of caspase 8 resulting in its activation. One of the small molecules identified demonstrated activity both in cancer cells that are resistant and cancer cells that are sensitive to caspase-dependent cell death induced by TRAIL. These results taken in sum provide insight into the structure-function relationship of caspase 8 homodimers as a putative target in drug strategies for targeting cancer
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