Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-κB signaling by degrading TRAF2-associated cIAP1 in cancer cells.
The inhibitor of apoptosis (IAP) proteins have pivotal roles in cell proliferation and differentiation, and antagonizing IAPs in certain cancer cell lines results in induction of cell death. A variety of IAP antagonist compounds targeting the baculovirus IAP protein repeat 3 (BIR3) domain of cIAP1have advanced into clinical trials. Here we sought to compare and contrast the biochemical activities of selected monovalent and bivalent IAP antagonists with the intent of identifying functional differences between these two classes of IAP antagonist drug candidates. The anti-cellular IAP1 (cIAP1) and pro-apoptotic activities of monovalent IAP antagonists were increased by using a single covalent bond to combine the monovalent moieties at the P4 position. In addition, regardless of drug concentration, treatment with monovalent compounds resulted in consistently higher levels of residual cIAP1 compared with that seen following bivalent compound treatment. We found that the remaining residual cIAP1 following monovalent compound treatment was predominantly tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2)-associated cIAP1. As a consequence, bivalent compounds were more effective at inhibiting TNF-induced activation of p65/NF-κB compared with monovalent compounds. Moreover, extension of the linker chain at the P4 position of bivalent compounds resulted in a decreased ability to degrade TRAF2-associated cIAP1 in a manner similar to monovalent compounds. This result implied that specific bivalent IAP antagonists but not monovalent compounds were capable of inducing formation of a cIAP1 E3 ubiquitin ligase complex with the capacity to effectively degrade TRAF2-associated cIAP1. These results further suggested that only certain bivalent IAP antagonists are preferred for the targeting of TNF-dependent signaling for the treatment of cancer or infectious diseases.
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Mitsuuchi
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Benetatos
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Deng
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Haimowitz
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Beck
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Arnone
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Kapoor
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Seipel
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Chunduru
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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McKinlay
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Begley
TetraLogic Pharmaceuticals Corporation , 343 Phoenixville Pike, Malvern, PA 19355, USA.
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Condon