To test the activity of the (+)-JQ1-MALAT1 gapmer conjugate, we measured MALAT1 transcript levels using reverse transcription-quantitative polymerase chain reaction (RT-qPCR) at 24 hours, comparing the knockdown to the unconjugated and azido-modified MALAT1 gapmer, normalised to the house keeping gene GAPDH. As with the SSO conjugate, the (+)-JQ1-MALAT1 gapmer conjugate outperformed the unconjugated and azido-modified MALAT1 gapmer at all tested concentrations. We measured 20.1%, 30.2%, 56.8%, and 54% less transcript with the (+)-JQ1 modified gapmer treatment, compared to the unmodified gapmer, at 5, 50, 100, and 200 nM respectively (Figure , SI Figure ). Again, similar to the 20 SSO, this enhanced activity was found to depend on specific (+)-JQ1-BET bromodomain protein interactions, as it was lost in the presence of excess quantities of small molecule (+)-JQ1. At 200 nM (+)-JQ1, the enhanced activity of the (+)-JQ1-MALAT1 gapmer at 50, 100, and 200 nM was completely inhibited (Figure , SI Figure ). Furthermore, little to no increase in toxicity was observed for the (+)-JQ1-MALAT1 gapmer conjugate, compared to the unconjugated MALAT1 gapmer at all concentrations (SI Figure ). This demonstrated that (+)-JQ1 conjugation can effectively increase both the While MALAT1 ASOs are being evaluated for their therapeutic applications, Oblimersen (G3139), an 18-mer ASO containing a fully PS backbone designed to target apoptosis factor BCL-2, reached phase III clinical trials (Figure ). BCL-2 is a crucial inhibitor of apoptosis that is overexpressed in various cancers. Despite promising phase I-II results as a 5 sensitiser for chemotherapy, G3139 failed to show efficacy in multiple phase III trails. As this drug was well tolerated by patients , the limiting factor is likely target engagement and efficacy. Therefore, given that G3139 functions as an RNase H-active ASO, like the MALAT1 gapmer, we aimed to determine whether a (+)-JQ1-G3139 conjugate could result in a more potent drug molecule.