It initially showed promise in preclinical trials, was used in phase I and phase II studies of hematologic and solid cancers, and ultimately did make it to phase III trials for metastatic colorectal cancer. While the drug was well tolerated, its ability to significantly reduce the growth of cancer over standard regimens was unimpressive, and it remains an experimental drug. While its clinical role remains unclear, SU5416 continues to be utilized in laboratory studies to confirm the importance of VEGF in various mechanistic studies, including cell trafficking, organ rejection, and autoimmunity. The data presented in this manuscript demonstrate that SU5416 is a strong ligand of the AHR. The unique finding that SU5416 binds the high- and low-affinity polymorphisms of the AHR similarly was rather surprising to us, and will require further attention and characterization. The mouse AHR can arise from an allele that encodes a receptor with high MCB-613 binding affinity for ligand or with low binding affinity for ligand. The AHRd is known to have approximately one-fifteenth to one-twentieth the binding affinity to TCDD as the AHRb, and this low affinity polymorphism resembles the isoform found in humans. C57BL/6 mice harbor the high-affinity AHRb receptor, and this MCE Chemical ML264 strain has been utilized for much of the initial characterization of TCDD and other environmental toxicants. In our search for relevant ligands of the AHR, we decided to focus on those that had significant potency in the AHRd isoform, as these ligands would have more clinical relevance in humans. We inadvertently identified that SU5416 had similar binding characteristics with both polymorphisms at doses that are similar to what were used in humans in Phase I trials with SU5416, as seen in the titration in figure 3D. This is an unusual characteristic that has rarely been exhibited by any of the known ligands of the AHR. The importance of this is due to the following: First, the information is clinically significant given that humans harbor an AHR isoform that more similarly represents the AHRd. Second, its structure will serve as a model in our search for endogenous ligands of the AHR. It makes sense that a true endogenous ligand would activate both polymorphisms of the AHR sim
