Overcoming Drug Resistance through the Development of Selective Inhibitors of UDP-Glucuronosyltransferase Enzymes.

ABSTRACT: Drug resistance is a major cause of cancer-related mortality. Glucuronidation of drugs via elevation of UDP-glucuronosyltransferases (UGT1As) correlates with clinical resistance. The nine UGT1A family members have broad substrate specificities attributed to their variable N-terminal domains and share a common C-terminal domain. Development of UGT1As as pharmacological targets has been hampered by toxicity of pan-UGT inhibitors and by difficulty in isolating pure N-terminal domains or full-length proteins. Here, we developed a strategy to target selected UGT1As which exploited the biochemical tractability of the C-domain and its ability to allosterically communicate with the catalytic site. By combining NMR fragment screening with in vitro glucuronidation assays, we identified inhibitors se

SUBMITTER: Osborne MJ 

PROVIDER: S-EPMC6331242 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature