Non-BRD4 messenger RNAs with partial sequence complementarity

Non-BRD4 messenger RNAs (mRNAs) with partial sequence complementarity refer to a diverse group of cellular transcripts that possess nucleotide sequences similar enough to a BRD4-targeting drug to allow for unintended binding (Jackson, A. L., & Linsley, P. S. 2010. Nat Rev Drug Discov). This phenomenon is primarily associated with nucleic acid-based therapeutics, such as antisense oligonucleotides (ASOs) or small interfering RNAs (siRNAs), which rely on Watson-Crick base pairing for specificity (Bennett, C. F., et al. 2017. Annu Rev Pharmacol Toxicol). When these drugs hybridize with non-target mRNAs, they can trigger degradation through mechanisms like RNase H-mediated cleavage or the RNA-induced silencing complex (RISC), leading to the depletion of proteins unrelated to the intended BRD4 target (Hong, D., et al. 2016. Cancer Res). Such off-target interactions are a critical concern in drug development because they can result in unpredictable toxicities, including hepatotoxicity or nephrotoxicity, depending on the function of the affected genes (Kurreck, J. 2003. Eur J Biochem). Consequently, this category of molecules is viewed as a significant safety hurdle and a primary focus of specificity screening during the preclinical development of BRD4-targeted genetic medicines (Watts, J. K., & Corey, D. R. 2012. J Pathol).

Other names

Off-target mRNAsNon-specific RNA transcriptsPartial match transcriptsOff-targetome

Unintended hybridization of antisense sequences to non-target mRNA transcripts leading to RNase H-mediated degradation or translational repression (Bennett, C. F., et al. 2017. Annu Rev Pharmacol Toxicol).