title: Birinapant (TL32711), a bivalent SMAC mimetic, targets TRAF2-associated cIAPs, abrogates TNF-induced NF-κB activation, and is active in patient-derived xenograft models.
abstract: The acquisition of apoptosis resistance is a fundamental event in cancer development. Among the mechanisms used by cancer cells to evade apoptosis is the dysregulation of inhibitor of apoptosis (IAP) proteins. The activity of the IAPs is regulated by endogenous IAP antagonists such as SMAC (also termed DIABLO). Antagonism of IAP proteins by SMAC occurs via binding of the N-terminal tetrapeptide (AVPI) of SMAC to selected BIR domains of the IAPs. Small molecule compounds that mimic the AVPI motif of SMAC have been designed to overcome IAP-mediated apoptosis resistance of cancer cells. Here, we report the preclinical characterization of birinapant (TL32711), a bivalent SMAC-mimetic compound currently in clinical trials for the treatment of cancer. Birinapant bound to the BIR3 domains of cIAP1, cIAP2, XIAP, and the BIR domain of ML-IAP in vitro and induced the autoubiquitylation and proteasomal degradation of cIAP1 and cIAP2 in intact cells, which resulted in formation of a RIPK1:caspase-8 complex, caspase-8 activation, and induction of tumor cell death. Birinapant preferentially targeted the TRAF2-associated cIAP1 and cIAP2 with subsequent inhibition of TNF-induced NF-κB activation. The activity of a variety of chemotherapeutic cancer drugs was potentiated by birinapant both in a TNF-dependent or TNF-independent manner. Tumor growth in multiple primary patient-derived xenotransplant models was inhibited by birinapant at well-tolerated doses. These results support the therapeutic combination of birinapant with multiple chemotherapies, in particular, those therapies that can induce TNF secretion.
authors.affiliation: Authors' Affiliations: TetraLogic Pharmaceuticals, 343 Phoenixville Pike, Malvern, Pennsylvania; and Tsinghua University School of Medicine, Beijing, China.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Benetatos
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mitsuuchi
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Burns
authors.forename: Eric M
authors.initials: EM
authors.lastname: Neiman
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Condon
authors.forename: Guangyao
authors.initials: G
authors.lastname: Yu
authors.forename: Martin E
authors.initials: ME
authors.lastname: Seipel
authors.forename: Gurpreet S
authors.initials: GS
authors.lastname: Kapoor
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Laporte
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rippin
authors.forename: Yijun
authors.initials: Y
authors.lastname: Deng
authors.forename: Mukta S
authors.initials: MS
authors.lastname: Hendi
authors.forename: Pavan K
authors.initials: PK
authors.lastname: Tirunahari
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Lee
authors.forename: Thomas
authors.initials: T
authors.lastname: Haimowitz
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Alexander
authors.forename: Martin A
authors.initials: MA
authors.lastname: Graham
authors.forename: David
authors.initials: D
authors.lastname: Weng
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
authors.forename: Mark A
authors.initials: MA
authors.lastname: McKinlay
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Chunduru
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D008819:Mice, Nude; D024101:Mitochondrial Proteins / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D007211:Indoles; D051034:Inhibitor of Apoptosis Proteins; D024101:Mitochondrial Proteins; D018124:Receptors, Tumor Necrosis Factor; D047992:TNF Receptor-Associated Factor 2; C582429:birinapant; D053181:Caspase 8