2. Academic Validation
  3. Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies

Revealing Metabolic Liabilities of Ralaniten To Enhance Novel Androgen Receptor Targeted Therapies

  • ACS Pharmacol Transl Sci. 2019 Sep 26;2(6):453-467. doi: 10.1021/acsptsci.9b00065.
Jon K Obst 1 2,  Jun Wang 1,  Kunzhong Jian 3,  David E Williams 3,  Amy H Tien 1,  Nasrin Mawji 1,  Teresa Tam 1,  Yu Chi Yang 1,  Raymond J Andersen 3,  Kim N Chi 4,  Bruce Montgomery 5,  Marianne D Sadar 1 2
Affiliations

Affiliations

  • 1 Department of Genome Sciences Centre, BC Cancer Research Centre, 675 W 10th Avenue, Vancouver, British Columbia V5Z 1L3, Canada.
  • 2 Department of Pathology and Laboratory Medicine, University of British Columbia, 2211 Westbrook Mall, Vancouver, British Columbia V6T 2B5, Canada.
  • 3 Departments of Chemistry and Earth, Ocean & Atmospheric Sciences, University of British Columbia, 2306 Main Mall, Vancouver, British Columbia V6T 1Z1, Canada.
  • 4 BC Cancer Agency, 600 West 10th Avenue, Vancouver, British Columbia V5Z 4E6, Canada.
  • 5 University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195, United States.
PMID: 32259077 DOI: 10.1021/acsptsci.9b00065
Abstract

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 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.

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