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. Author manuscript; available in PMC: 2021 Jul 28.
Published in final edited form as: J Am Chem Soc. 2021 Mar 19;143(12):4714–4724. doi: 10.1021/jacs.1c00312

Figure 1. Design, synthesis, and OTX-015 release profiles for BETi-BPDs B1–B4.

Figure 1.

(a) Design and synthesis of OTX-015-based brush prodrugs B1–B4. Azido-acids (shown in blue) are used to form ester or carbonate conjugates with OTX-015. Cu-catalyzed azide-alkyne cycloaddition to a PEG-alkyne macromonomer (MM) generates B1–B4 MMs. Ring-opening metathesis polymerization (ROMP) of each MM in the presence of a Cy7.5-labeled MM (1 mol %) generates BETi-BPDs B1–B4. (b) Careful linker design enables modulation of OTX-015 release half-lives. (c) Release of BET inhibitors in vitro (saline buffer, 37 °C). (d) Linker composition modulates serum stability. Blood levels of free OTX-015 drug released from B4 at peak concentration (0.5 h post administration) is lower than the peak concentrations observed after equivalent doses of B2, B3, and lower compared to the maximum tolerated p.o. dose of OTX-015 at 2 or 3 h. (e) B4 displays higher levels of released OTX-015 in tumor tissue compared to B2 and B3, 72 hours after last dose of brush prodrugs. Statistical analysis performed using unpaired t test. Any p-values not shown are n.s.; * p<0.05, *** p<0.001; error bars represent SD.