ORIC Pharmaceuticals Presents Preclinical Data On Two Programs At The 2024 AACR Annual Meeting

Author: Benzinga Newsdesk | April 08, 2024 08:15am

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

 

Preclinical synergy data in prostate cancer models reinforces the promise of ORIC-944 as a potential best-in-class treatment for combinations with AR 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."

Presentation details:

ORIC-944: a potent and selective allosteric inhibitor of PRC2

Discovery of ORIC-944, a novel inhibitor of PRC2 with potential best-in-class properties for the treatment of prostate cancer

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:
  • Strong potency with 106 picomolar EC50 in biochemical binding assay
  • Superior solubility, oral bioavailability, half-life, and CYP profile in preclinical studies
  • Clinical half-life estimated at approximately 20 hours, with no sign of CYP autoinduction that is observed with first-generation PRC2 inhibitors
  • Results from combinations with an AR inhibitor in an in vivo prostate model shows ORIC-944 provides better activity than PF-06821497
• 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
  • Synergy was observed both in vitro and in vivo for ORIC-944 in combination with AR inhibitors in prostate cancer models
• These results position ORIC-944 as a potential best-in-class PRC2 inhibitor for combination with AR inhibitors in patients with prostate cancer
  
   

ORIC-613: a potent and selective PLK4 inhibitor

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
• ORIC-613 has superior kinome selectivity versus comparator compounds CFI-400945 and RP-1664
• 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
• Oral dosing of ORIC-613 at 150 mg/kg QD resulted in tumor regressions and tumor growth inhibition in TRIM37-high xenograft breast tumors
• ORIC-613 retained potency in breast cancer models resistant to CDK4/6 inhibitors
  • 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

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