Ameliorating Toxicity

Regorafenib, Stivarga, is an oral small molecule kinase inhibitor used to treat metastatic colorectal cancer, hepatocellular carcinomas, and gastrointestinal stromal tumors. Diarrhea is one of the most frequently observed adverse reactions associated with regorafenib. This toxicity may arise from the reactivation of the inactive regorafenib-glucuronide to regorafenib by gut microbial β-glucuronidase, GUS, enzymes in the gastrointestinal tract.

Researchers in the Redinbo Lab, in collaboration with colleagues from UNC's Eshelman School of Pharmacy, in a paper published in ACS Chemical Biology, seek to unravel the molecular basis of regorafenib-glucuronide processing by human intestinal GUS enzymes and to examine the potential inhibition of these enzymes.

Professor Redinbo's research on the gut microbiome, is not only widely recognized, it has a compelling personal aspect. Please read the following recent articles from Scientific American, and Chemical and Engineering News, C&EN to learn more.

Using a panel of 31 unique gut microbial GUS enzymes derived from the 279 mapped from the human gut microbiome, the researchers found that only four were capable of regorafenib-glucuronide processing. Using crystal structures as a guide, group members pinpointed the molecular features unique to these enzymes that confer regorafenib-glucuronide processing activity.

Furthermore, a pilot screen identified the FDA-approved drug raloxifene as an inhibitor of regorafenib reactivation by the GUS proteins discovered. Novel synthetic raloxifene analogs exhibited improved potency in both in vitro and ex vivo studies.

Taken together, these data establish that regorafenib reactivation is exclusively catalyzed by gut microbial enzymes and that these enzymes are amenable to targeted inhibition. These results unravel key molecular details of regorafenib reactivation in the GI tract and provide a potential pathway to improve clinical outcomes with regorafenib.