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Updated: Feb 6, 2026

Biochemical Reconstitution of Steroid Receptor•Hsp90 Protein Complexes and Reactivation of Ligand Binding
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Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101)

Yosup Rew1, Xiaohui Du1, John Eksterowicz1

  • 1ORIC Pharmaceuticals , 240 East Grand Avenue, Fl2 , South San Francisco , California 94080 , United States.

Journal of Medicinal Chemistry
|August 10, 2018
PubMed

Insights

A novel glucocorticoid receptor (GR) antagonist, ORIC-101, shows promise in enhancing cancer therapy. This compound demonstrates improved safety and efficacy, particularly with chemotherapy, in preclinical models.

Area of Science:

  • Oncology
  • Endocrinology
  • Pharmacology

Background:

  • Glucocorticoid receptor (GR) signaling is implicated in cancer therapy resistance.
  • Existing GR antagonists like mifepristone have limitations for clinical oncology use.
  • There is a need for GR antagonists with improved drug interaction profiles and efficacy.

Purpose of the Study:

  • To discover and characterize novel, potent GR antagonists.
  • To develop a GR antagonist suitable for co-administration with chemotherapy.
  • To evaluate the in vivo antitumor activity of the novel antagonist.

Main Methods:

  • Structure-based drug design and modification of mifepristone.
  • In vitro characterization of antagonist potency, selectivity (GR vs. AR), and drug metabolism enzyme inhibition (CYP2C8, CYP2C9).
  • In vivo efficacy studies using ovarian cancer xenograft models (GR+ OVCAR5) in combination with chemotherapy.

Main Results:

  • ORIC-101 (28) was identified as a potent steroidal GR antagonist.
  • ORIC-101 exhibits reduced androgen receptor (AR) agonistic activity compared to mifepristone.
  • ORIC-101 has an improved drug-drug interaction profile, allowing co-administration with CYP2C8 substrates like paclitaxel.
  • ORIC-101 enhanced chemotherapy response in a preclinical ovarian cancer model.

Conclusions:

  • ORIC-101 is a potent GR antagonist with a favorable pharmacological profile.
  • ORIC-101 demonstrates potential to overcome therapy resistance and enhance chemotherapy efficacy.
  • Further clinical evaluation of ORIC-101 for cancer treatment is warranted.

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