pt9b00065_si_001.pdf (919.98 kB)
Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies
journal contribution
posted on 2019-10-09, 14:35 authored by Jon K. Obst, Jun Wang, Kunzhong Jian, David E. Williams, Amy H. Tien, Nasrin Mawji, Teresa Tam, Yu Chi Yang, Raymond J. Andersen, Kim N. Chi, Bruce Montgomery, Marianne D. SadarInhibition
of the androgen receptor (AR) is the mainstay treatment
for advanced prostate cancer. Ralaniten (formally EPI-002) prevents
AR transcriptional activity by binding to its N-terminal domain (NTD)
which is essential for transcriptional activity. Ralaniten acetate
(EPI-506) the triacetate pro-drug of ralaniten, remains the only AR-NTD
inhibitor to have entered clinical trials (NCT02606123). While well
tolerated, the trial was ultimately terminated due to poor pharmacokinetic
properties and resulting pill burden. Here we discovered that ralaniten
was glucuronidated which resulted in decreased potency. Long-term
treatment of prostate cancer cells with ralaniten results in upregulation
of UGT2B enzymes with concomitant loss of potency. This has proven
to be a useful model with which to facilitate the development of more
potent second-generation AR-NTD inhibitors. Glucuronidated metabolites
of ralaniten were also detected in the serum of patients in Phase
1 clinical trials. Therefore, we tested an analogue of ralaniten (EPI-045)
which was resistant to glucuronidation and demonstrated superiority
to ralaniten in our resistant model. These data support that analogues
of ralaniten designed to mitigate glucuronidation may optimize clinical
responses to AR-NTD inhibitors.
History
Usage metrics
Categories
Keywords
androgen receptorralaniten resultstriacetate pro-drugEPIRevealing Metabolic Liabilitiespharmacokinetic propertiesprostate cancer cellsAR-NTD inhibitorsAR-NTD inhibitorN-terminal domainEnhance Novel Androgen Receptor Targeted Therapies Inhibitionsecond-generation AR-NTD inhibitorsdata supportRalaniten acetatePhase 1pill burdenAR transcriptional activityUGT 2B enzymesprostate cancertranscriptional activitymainstay treatmentLong-term treatmentNCTGlucuronidated metabolites
Licence
Exports
RefWorks
BibTeX
Ref. manager
Endnote
DataCite
NLM
DC