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

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.