Birinapant, a Smac-Mimetic with Improved Tolerability for the Treatment of Solid Tumors and Hematological Malignancies Academic Article uri icon

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

  • Condon, SM
  • Mitsuuchi, Y
  • Deng, Y
  • LaPorte, MG
  • Rippin, SR
  • Haimowitz, T
  • Alexander, MD
  • Kumar, PT
  • Hendi, MS
  • Lee, Y-H
  • Benetatos, CA
  • Yu, G
  • Kapoor, GS
  • Neiman, E
  • Seipel, ME
  • Burns, JM
  • Graham, MA
  • McKinlay, MA
  • Li, X
  • Wang, J
  • Shi, Y
  • Feltham, R
  • Bettjeman, B
  • Cumming, MH
  • Vince, JE
  • Khan, N
  • Silke, J
  • Day, CL
  • Chunduru, SK

publication date

  • 2014