2. Academic Validation
  3. Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101)

Discovery of a Potent and Selective Steroidal Glucocorticoid Receptor Antagonist (ORIC-101)

  • J Med Chem. 2018 Sep 13;61(17):7767-7784. doi: 10.1021/acs.jmedchem.8b00743.
Yosup Rew 1,  Xiaohui Du 1,  John Eksterowicz 1,  Haiying Zhou 1,  Nadine Jahchan 1,  Liusheng Zhu 1,  Xuelei Yan 1,  Hiroyuki Kawai 1,  Lawrence R McGee 1,  Julio C Medina 1,  Tom Huang 1,  Chelsea Chen 1,  Tatiana Zavorotinskaya 1,  Dena Sutimantanapi 1,  Joanna Waszczuk 1,  Erica Jackson 1,  Elizabeth Huang 1,  Qiuping Ye 1,  Valeria R Fantin 1,  Daqing Sun 1
Affiliations

Affiliation

  • 1 ORIC Pharmaceuticals , 240 East Grand Avenue, Fl2 , South San Francisco , California 94080 , United States.
PMID: 30091920 DOI: 10.1021/acs.jmedchem.8b00743
Abstract

The Glucocorticoid Receptor (GR) has been linked to therapy resistance across a wide range of Cancer types. Preclinical data suggest that antagonists of this nuclear receptor may enhance the activity of Anticancer therapy. The first-generation GR antagonist mifepristone is currently undergoing clinical evaluation in various oncology settings. Structure-based modification of mifepristone led to the discovery of ORIC-101 (28), a highly potent steroidal GR antagonist with reduced Androgen Receptor (AR) agonistic activity amenable for dosing in Androgen Receptor positive tumors and with improved CYP2C8 and CYP2C9 inhibition profile to minimize drug-drug interaction potential. Unlike mifepristone, 28 could be codosed with chemotherapeutic agents readily metabolized by CYP2C8 such as paclitaxel. Furthermore, 28 demonstrated in vivo antitumor activity by enhancing response to chemotherapy in the GR+ OVCAR5 ovarian Cancer xenograft model. Clinical evaluation of safety and therapeutic potential of 28 is underway.

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