AEG35156 (DB06184): A Comprehensive Review of a Second-Generation XIAP-Targeting Antisense Oligonucleotide

1. Introduction to AEG35156 (DB06184)

Overview: AEG35156 as a Second-Generation Antisense Oligonucleotide (ASO)

AEG35156 (DrugBank ID: DB06184) is an investigational therapeutic agent classified as a second-generation synthetic antisense oligonucleotide (ASO).[1] These second-generation ASOs were engineered to overcome limitations of earlier ASO chemistries, primarily by incorporating chemical modifications that enhance their stability against nuclease degradation, improve binding affinity to target messenger RNA (mRNA), and potentially offer a more favorable toxicity profile.[4] Such improvements are critical for achieving therapeutic efficacy in a clinical setting. AEG35156 was specifically designed with the potential for antineoplastic activity by selectively interfering with the cellular expression of a key protein implicated in cancer cell survival and drug resistance.[1]

Therapeutic Target: X-linked Inhibitor of Apoptosis Protein (XIAP)

The molecular target of AEG35156 is the mRNA encoding the X-linked Inhibitor of Apoptosis Protein (XIAP), also known as Baculoviral IAP Repeat Containing 4 (BIRC4) or Inhibitor of Apoptosis Protein 3 (IAP3).[1] XIAP is recognized as one of the most potent endogenous inhibitors of apoptosis (programmed cell death). Its primary anti-apoptotic function is executed through the direct binding and inhibition of key executioner caspases, namely caspase-3 and caspase-7, as well as the initiator caspase-9.[1] By neutralizing these critical enzymes, XIAP effectively blocks the progression of both the intrinsic (mitochondrial) and extrinsic (death receptor-mediated) apoptotic pathways, thereby promoting cell survival.

Rationale for Targeting XIAP in Cancer