Obst, Jon K. published the artcileRevealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies, Safety of (R)-Oxiran-2-ylmethanol, the publication is ACS Pharmacology & Translational Science (2019), 2(6), 453-467, database is CAplus and MEDLINE.
Inhibition 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 clin. 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 clin. trials. Therefore, we tested an analog of ralaniten (EPI-045) which was resistant to glucuronidation and demonstrated superiority to ralaniten in our resistant model. These data support that analogs of ralaniten designed to mitigate glucuronidation may optimize clin. responses to AR-NTD inhibitors.
ACS Pharmacology & Translational Science published new progress about 57044-25-4. 57044-25-4 belongs to alcohols-buliding-blocks, auxiliary class Epoxides,Chiral,Aliphatic hydrocarbon chain,Alcohol, name is (R)-Oxiran-2-ylmethanol, and the molecular formula is C3H6O2, Safety of (R)-Oxiran-2-ylmethanol.
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