Birinapant/TL32711is a novel bivalent antagonist of the inhibitor of apoptosis (IAP) family of proteins.  The IAPs block tumor cell apoptosis (or, programmed cell death) by inhibiting the activation of caspase enzymes. IAP activity is modulated by the second mitochondria-derived activator of caspases (or, Smac). The N-terminal tetrapeptide of Smac, i.e., Ala-Val-Pro-Ile (AVPI), binds to the IAPs which allows for caspase activation.  Birinapant was thus designed to mimic the AVPI tetrapeptide motif of Smac.  Birinapant treatment induced the rapid degradation of cIAP1, which correlated with inhibition of TNF-mediated NF-kB activation, caspase activation and tumor cell apoptosis in vitro and in vivo.  Birinapant is currently undergoing clinical development for the treatment of both solid and hematological cancers.  To support our clinical program, a GMP process for the large-scale synthesis of birinapant was required.  The synthesis was divided into two sections: i. conversion of Cbz-Hyp-OH into the biindole-containing intermediate; and, ii. addition of the two requisite dipeptide chains to furnish birinapant API.  Using this process, birinapant API has been prepared multiple times under good manufacturing practice (GMP) at >500 g-scale. The evolution of this process from the initial discovery route as well as a detailed discussion of several key observations will be described.  

Process development of birinapant/TL32711: A novel smac-mimetic for the treatment of cancer

248th National Meeting (2014)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.