Birinapant, a smac-mimetic with improved tolerability for the treatment of solid tumors and hematological malignancies

Stephen M. Condon, Yasuhiro Mitsuuchi, Yijun Deng, Matthew G. Laporte, Susan R. Rippin, Thomas Haimowitz, Matthew D. Alexander, Pavan Tirunahari Kumar, Mukta S. Hendi, Yu Hua Lee, Christopher A. Benetatos, Guangyao Yu, Gurpreet Singh Kapoor, Eric Neiman, Martin E. Seipel, Jennifer M. Burns, Martin A. Graham, Mark A. McKinlay, Xiaochun Li, Jiawei WangYigong Shi, Rebecca Feltham, Bodhi Bettjeman, Mathew H. Cumming, James E. Vince, Nufail Khan, John Silke, Catherine L. Day, Srinivas K. Chunduru

Research output: Contribution to journalArticlepeer-review

125 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)3666-3677
Number of pages12
JournalJournal of Medicinal Chemistry
Issue number9
StatePublished - May 8 2014

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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