title: A novel caspase 8 selective small molecule potentiates TRAIL-induced cell death.
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.
authors.affiliation: 1] Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA [2] Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
authors.forename: Octavian
authors.initials: O
authors.lastname: Bucur
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Gaidos
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Achani
authors.initials: A
authors.lastname: Yatawara
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Bodvael
authors.initials: B
authors.lastname: Pennarun
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Chamila
authors.initials: C
authors.lastname: Rupasinghe
authors.affiliation: Department of Systems Biology, Harvard Medical School, Boston, MA, USA.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Roux
authors.affiliation: Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Andrei
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Bingqian
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Panaitiu
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Pellegrini
authors.affiliation: Department of Chemistry, Dartmouth College, Hanover, NH, USA.
authors.forename: Dale F
authors.initials: DF
authors.lastname: Mierke
authors.affiliation: 1] Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA [2] Department of Biological and Biomedical Sciences Program, Harvard Medical School, Boston, MA, USA.
authors.forename: Roya
authors.initials: R
authors.lastname: Khosravi-Far
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D053181:Caspase 8 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000235:genetics; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D020014:K562 Cells; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism*
chemical_list: D020536:Enzyme Activators; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C105190:TNFRSF10A protein, human; C505653:TNFSF10 protein, human; C505530:CASP8 protein, human; D053181:Caspase 8