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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 3. Blood cell populations and gut versus tumor biomarker assessments of B4 and OTX-015.

Figure 3.

(a) Analysis of blood cell populations demonstrates that unlike the parent free OTX-015 drug, the B4 prodrug does not cause the systemic toxicity associated with BET inhibition. No reduction in platelet, reticulocyte, neutrophil, and lymphocyte levels were detected (n=5) at doses resulting in superior anti-tumor efficacy of B4 compared to free API; error bars represent SD. (b)(c) B4 causes only minimal intestinal toxicity compared to OTX-015 as evidenced by in situ protein expression of c-Myc, a PD biomarker for BET inhibition, in the base of crypts and preserved colonic villus epithelial surface morphology. Anti-tumor efficacy of B4 prodrug is comparable to free OTX-015 as shown by modulation of PD markers c-Myc, HEXIM1, and CD180 levels in extracted tumors. Statistical analysis performed using unpaired t test for tumor volumes and c-Myc expression and using Welch’s t test for assessment of hematologic toxicity; all groups compared to the vehicle group except where indicated otherwise. Any p-values not shown are n.s.; * p<0.05, ** p<0.01, *** p<0.001, **** p<0.001. Scale bars: 100 μm.