title: Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies.
abstract: Birinapant (1) is a second-generation bivalent antagonist of IAP proteins that is currently undergoing clinical development for the treatment of cancer. Using a range of assays that evaluated cIAP1 stability and oligomeric state, we demonstrated that 1 stabilized the cIAP1-BUCR (BIR3-UBA-CARD-RING) dimer and promoted autoubiquitylation of cIAP1 in vitro. Smac-mimetic 1-induced loss of cIAPs correlated with inhibition of TNF-mediated NF-κB activation, caspase activation, and tumor cell killing. Many first-generation Smac-mimetics such as compound A (2) were poorly tolerated. Notably, animals that lack functional cIAP1, cIAP2, and XIAP are not viable, and 2 mimicked features of triple IAP knockout cells in vitro. The improved tolerability of 1 was associated with (i) decreased potency against cIAP2 and affinity for XIAP BIR3 and (ii) decreased ability to inhibit XIAP-dependent signaling pathways. The P2' position of 1 was critical to this differential activity, and this improved tolerability has allowed 1 to proceed into clinical studies.
authors.affiliation: TetraLogic Pharmaceuticals, Inc. , 343 Phoenixville Pike, Malvern, Pennsylvania 19355, United States.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Condon
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Mitsuuchi
authors.forename: Yijun
authors.initials: Y
authors.lastname: Deng
authors.forename: Matthew G
authors.initials: MG
authors.lastname: LaPorte
authors.forename: Susan R
authors.initials: SR
authors.lastname: Rippin
authors.forename: Thomas
authors.initials: T
authors.lastname: Haimowitz
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Alexander
authors.forename: Pavan Tirunahari
authors.initials: PT
authors.lastname: Kumar
authors.forename: Mukta S
authors.initials: MS
authors.lastname: Hendi
authors.forename: Yu-Hua
authors.initials: YH
authors.lastname: Lee
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Benetatos
authors.forename: Guangyao
authors.initials: G
authors.lastname: Yu
authors.forename: Gurpreet Singh
authors.initials: GS
authors.lastname: Kapoor
authors.forename: Eric
authors.initials: E
authors.lastname: Neiman
authors.forename: Martin E
authors.initials: ME
authors.lastname: Seipel
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Burns
authors.forename: Martin A
authors.initials: MA
authors.lastname: Graham
authors.forename: Mark A
authors.initials: MA
authors.lastname: McKinlay
authors.forename: Xiaochun
authors.initials: X
authors.lastname: Li
authors.forename: Jiawei
authors.initials: J
authors.lastname: Wang
authors.forename: Yigong
authors.initials: Y
authors.lastname: Shi
authors.forename: Rebecca
authors.initials: R
authors.lastname: Feltham
authors.forename: Bodhi
authors.initials: B
authors.lastname: Bettjeman
authors.forename: Mathew H
authors.initials: MH
authors.lastname: Cumming
authors.forename: James E
authors.initials: JE
authors.lastname: Vince
authors.forename: Nufail
authors.initials: N
authors.lastname: Khan
authors.forename: John
authors.initials: J
authors.lastname: Silke
authors.forename: Catherine L
authors.initials: CL
authors.lastname: Day
authors.forename: Srinivas K
authors.initials: SK
authors.lastname: Chunduru
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000737:chemistry*; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D055808:Drug Discovery; D019337:Hematologic Neoplasms / Q000188:drug therapy*; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D024101:Mitochondrial Proteins / Q000737:chemistry*; D008958:Models, Molecular; D018716:Molecular Mimicry; D009374:Neoplasms, Experimental / Q000188:drug therapy*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; C499605:Diablo protein, mouse; D004151:Dipeptides; D007211:Indoles; D024101:Mitochondrial Proteins; C582429:birinapant