ORIC Pharmaceuticals Presents Preclinical Data on Two Programs at the 2024 American Association for Cancer Research (AACR) Annual Meeting
Retrieved on:
Monday, April 8, 2024
SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, April 08, 2024 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced two oral presentations on ORIC-944, a potent and selective allosteric inhibitor of PRC2, and presentation of a new discovery candidate, ORIC-613, an orally bioavailable, potent and selective PLK4 inhibitor, at the 2024 American Association for Cancer Research (AACR) Annual Meeting.
Key Points:
- ORIC-944, a potent and selective allosteric PRC2 inhibitor, demonstrates superior preclinical drug properties and longer clinical half-life which supports a potential best-in-class profile versus competitor PRC2 inhibitors
First data presentation on ORIC-613, a potential first- and best-in-class development candidate selectively inhibiting PLK4
SOUTH SAN FRANCISCO, Calif. and SAN DIEGO, April 08, 2024 (GLOBE NEWSWIRE) -- ORIC Pharmaceuticals, Inc. (Nasdaq: ORIC), a clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, today announced two oral presentations on ORIC-944, a potent and selective allosteric inhibitor of PRC2, and presentation of a new discovery candidate, ORIC-613, an orally bioavailable, potent and selective PLK4 inhibitor, at the 2024 American Association for Cancer Research (AACR) Annual Meeting. - “ORIC-944 in combination with AR inhibitors demonstrates anti-tumor activity in multiple AR-positive prostate cancer models, supporting the planned expansion of our ORIC-944 clinical program in combination with AR inhibitors in metastatic prostate cancer,” said Lori Friedman, PhD, chief scientific officer.
- “These encouraging preclinical findings, coupled with potential best-in-class drug properties and deepened understanding of the mechanism driving synergy, fuel our optimism for advancing this program.
- Additionally, the unveiling of preclinical characterization of ORIC-613, a potential first- and best-in-class selective PLK4 inhibitor, marks a significant milestone in our discovery program, with preclinical data demonstrating synthetic lethality in TRIM37-high tumors.”
ORIC-944, a potent and selective allosteric PRC2 inhibitor with potential best-in-class properties, demonstrates combination synergy with AR pathway inhibitors in prostate cancer models (Presentation will be available on ORIC website on Tuesday, April 9, 2024 at 2:30 p.m. PT)
Key findings of the presentations:
Discovery of ORIC-944 was enabled through structure-based drug design and leveraged a cryptic pocket in an allosteric site in EED, a subunit of PRC2
Comprehensive profiling supports ORIC-944's best-in-class properties versus competitor PRC2 inhibitors, including PF-06821497, tazemetostat, and CPI-0209:
Clinical half-life estimated at approximately 20 hours, with no sign of CYP autoinduction that is observed with first-generation PRC2 inhibitors
Demonstrated that EED and EZH2 inhibitors act through the same mechanism of action, making prostate cancer cells more susceptible to AR inhibition:
Transcriptional changes induced by ORIC-944 were comparable to those of EZH2 inhibitors in prostate cancer models, indicating no mechanistic distinction between molecules targeting different core subunits of PRC2
RNA sequencing of prostate cancer models revealed that ORIC-944 increases AR signaling and luminal cell fate, thereby rendering these cells more susceptible to AR inhibition
ORIC-613, a potential first- and best-in-class, orally bioavailable, potent and selective PLK4 inhibitor with synthetic lethality in TRIM37 high cancer models
Key findings of the presentation:
ORIC-613 is an orally bioavailable, potent and exquisitely selective small molecule inhibitor of PLK4, which is synthetic lethal in tumor cells with high levels of TRIM37
Preclinical assessment in cancer cell lines revealed synthetic lethality, with ORIC-613 inducing apoptotic tumor cell death specifically in TRIM37-high breast cancer and neuroblastoma cells versus TRIM37-wildtype cells
These results position ORIC-613 as a potential first- and best-in-class development candidate, which has the potential to benefit patients with TRIM37-high tumors