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Targeting Regorafenib-Induced Toxicity through Inhibition of Gut Microbial β-Glucuronidases.

Abstract：

: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. We sought to unravel the molecular basis of regorafenib-glucuronide processing by human intestinal GUS enzymes and to examine the potential inhibition of these enzymes. Using a panel of 31 unique gut microbial GUS enzymes derived from the 279 mapped from the human gut microbiome, we found that only four were capable of regorafenib-glucuronide processing. Using crystal structures as a guide, we 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. Our results unravel key molecular details of regorafenib reactivation in the GI tract and provide a potential pathway to improve clinical outcomes with regorafenib.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Ervin SM,Hanley RP,Lim L,Walton WG,Pearce KH,Bhatt AP,James LI,Redinbo MR

doi

10.1021/acschembio.9b00663

subject

Has Abstract

pub_date

2019-12-20 00:00:00

pages

2737-2744

issue

12

eissn

1554-8929

issn

1554-8937

journal_volume

14

pub_type

杂志文章

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